Drug repurposing approach to fight COVID-19.

Introduction

Drug repurposing is the process to identify the new indications for existing drugs and considered as an efficient and economical approach [ 1 ]. It is also known as repositioning, re-profiling, re-tasking and rescue of drugs [ 2 ]. It has been considered that 75% of known drugs could be repositioned for various diseases [ 1 ]. Outbreaks of novel emerging infections such as coronavirus disease 2019 (COVID-19) have unique challenges in front of the health professionals to select appropriate therapeutics/pharmacological treatments in the clinical setup with very little time available for the new drug discovery [ 3 ]. Further, development of a vaccine for any disease including COVID-19 takes time and even if the process is put on accelerated mode it would take 18–20 months to introduce it as ready-to-use product. Currently, no specific treatment is available against the new virus severe acute respiratory syndrome coronavirus 2 (SARS-CoV2). Hence, the search for effective therapeutic agents to tackle COVID-19 is vital and urgent. The discovery and licensed use of a drug come with a long-gestation period. The cost of the new drug development process amounts to more than a billion dollars extending for a period of 10–15 years [ 4 ] with the success rate of only 2.01% [ 5 ]. This creates a lag in the productivity of pharmaceutical research to develop a new drug which results in a persistent gap between therapeutic needs and available treatments [ 6 ]. Considering the time and cost required for coming up with new therapies, probing the existing antiviral and other drugs against SARS-CoV2 is cost-effective. In recent times, repurposing of available drugs for the management of several disease conditions is increasingly becoming a popular strategy as it uses de-risked compounds with known preclinical, pharmacokinetic, pharmacodynamic profiles which can directly enter phase III or IV clinical trial making the drug development process potentially a low-cost and relatively rapid [ 7 ]. Therefore, reassessing the efficacy of licensed and experimental drugs has become go to choice of World Health Organization (WHO) and other health agencies to treat emerging health problems.

Drug repurposing follows mainly two concepts. One is that a single drug interacts with multiple targets, which paves the way for searching new target sites of action for the known compound [ 8 , 9 ]. The other concept is that targets associated with a disease are often relevant to a number of biological processes of pathogenesis [ 6 , 10 ] which paves the way for designation of a new indication for the known target. Notionally, a drug that acts on these common elements can, in principle, be useful for several disorders.

Different repurposing approaches

Broadly, there are three kinds of approaches which are widely used in drug repositioning: computational approaches, biological experimental approaches, and mixed approaches. Data such as gene expression, drug-target interactions, protein networks, electronic health records, clinical trial reports, and drug adverse event reports has become accessible in standardized forms. The repository of knowledge and omics data available in pharmaceutical research leads to the rise of some computational methods which are novel and exciting in the field of drug repositioning. These computational methods are capable to make a high-level integration of all the knowledge and data and help in understanding the new signaling pathways and generate novel insights into drug mechanisms, side effects, and interactions which further speed up drug discovery. A recent study presented integrative network-based systems pharmacology, methodology which quantifies the interplay between the coronavirus–human cell interactome and drug targets in the human protein–protein interaction network which help in rapid identification of repurposable drugs against SARS-CoV2. A study using this kind of approach was able to identify 30 potential repurposable drugs against COVID-19 [ 11 , 12 ].

The SARS-CoV2 mainly spreads through the respiratory tract [ 13 ] and affects alveolar cells. Unlike, Middle East respiratory syndrome coronavirus (MERS-CoV) which employs dipeptidyl peptidase 4 (DPP4) [ 14 ], SARS-CoV and SARS-CoV2 adopt angiotensin-converting enzyme 2 (ACE2) as receptor for entering the cell. Attachment, fusion and entry of the virus are aided by spike protein which makes it an interesting target for the development of antibodies, entry inhibitors and vaccines [ 15 ]. Anti-viral agents including ritonavir, lopinavir, ribavirin, interferons have been used against SARS-CoV and MERS-CoV clinically, however, clinical data is still limited [ 16 ]. Currently, with the lack of effective agents against SARS-CoV2 as well as public-health emergency, WHO has identified some therapies which doctors and researchers believe are the most promising, such as a combination of two HIV drugs (lopinavir and ritonavir), anti-malarial drugs (chloroquine and hydroxychloroquine), and an experimental antiviral compound remdesivir. Further, many available drugs with the intention of repurposing against COVID-19 have been subjected to clinical trials [ 17 ] (Table 1 ). However, the search for other agents cannot pause while waiting for the results because the demand for new effective agents is huge. Table 1 List of potential pharmacological agents that may be used against COVID-19/SARS-CoV2 infection Suggested class of drugs Drug Target Effect Tests conducted against SARS-CoV2/COVID-19 Clinical trials/ Phase of development Reference Drugs acting on viral replication Remdesivir RdRP Inhibits viral replication In-silico, in-vitro, humans NCT04292730 - Phase 3 NCT04292899 - Phase 3 NCT04401579 - Phase 3 [ 23 , 32 , 33 , 35 , 196 ] Favipiravir RdRP Inhibits viral replication In-silico, in-vitro, humans NCT04358549 - Phase 2 NCT04303299 - Phase 3 NCT04346628 - Phase 2 [ 29 , 41 , 199 – 201 ] Ribavirin Inosine monophosphate dehydrogenase, RdRP Inhibits viral replication In-silico, in-vitro, human IRCT20200324046850N2- Phase 2 NCT04276688 - Phase 2 NCT04392427 - Phase 3 [ 29 , 52 , 102 , 196 , 202 ] Elbasvir RdRP, papain-like proteinase and helicase (Based on molecular docking study) Blocks viral replication (probable) In-silico None [ 197 , 203 ] Cepharanthine Viral RNA (reducing plasma membrane fluidity in HIV), RDRP, main protease Blocks viral entry and replication In-silico, in-vitro None [ 181 , 204 – 206 ] IDX-184 RdRP, GTP binding (Based on molecular docking study) Blocks viral replication (probable) In-silico None [ 196 ] Sofosbuvir RdRP (Based on molecular docking study) Blocks viral replication (probable) In-silico, humans IRCT20100228003449N29- Phase 2–3 IRCT20130812014333N145- Phase 3 IRCT20200128046294N2- Phase 3 [ 196 , 207 , 208 ] Drugs acting on viral entry Lopinavir-ritonavir Protease Inhibits viral entry In-silico, in-vitro, humans NCT04372628 - Phase 2 NCT04276688 - Phase 2 NCT04330690 - Phase 2 [ 66 – 68 , 209 , 210 ] Darunavir Protease Inhibits viral entry In-silico, in-vitro, humans NCT04252274 - Phase 3 NCT04303299 - Phase 3 NCT04425382 [ 33 , 82 , 211 ], https://www.sd.chinanews.com/2/2020/0205/70145.html Arbidol Hemagglutinin fusion machinery, spike glycoprotein Inhibits viral entry In-silico, in-vitro, humans NCT04286503 - Phase 4 NCT04260594 - Phase 4 NCT04255017 - Phase 4 [ 124 , 127 , 131 , 212 , 213 ] Angiotensin Receptor Blockers Angiotensin converting enzyme Inhibits viral entry Humans NCT04335123 - Phase 1 NCT04312009 - Phase 2 NCT04428268 - Phase 2 [ 139 ] Nafamostat Prevents membrane fusion (MERS-CoV) Inhibits viral entry In-vitro, humans NCT04352400 - Phase 2 NCT04418128 - Phase 2 jRCTs031200026- Phase 3 [ 29 , 214 , 215 ] Chloroquine and hydroxychloroquine Change in endosomal pH; glycosylation of the host receptor for the virus, angiotensin converting enzyme 2 Inhibits viral entry as well as post entry In-silico, in-vitro, humans NCT04382625 - Phase 4 NCT04355026 - Phase 4 NCT04303299 - Phase 3 [ 33 , 106 – 108 , 199 , 216 ] Prulifloxacin Proteases (Based on molecular docking study) Blocks the active sites or interrupt the dimer formation of viral protein (probable) In-silico None [ 195 ] Tegobuvir Proteases (Based on molecular docking study) Blocks the active sites or interrupt the dimer formation of viral protein (probable) In-silico None [ 195 , 204 , 217 ] Nelfinavir Proteases (Based on molecular docking study) Blocks the active sites or interrupt the dimer formation of viral protein (probable) In-silico, in-vitro None [ 195 , 206 , 218 ] Bictegravir Proteases (Based on molecular docking study) Blocks the active sites or interrupt the dimer formation of viral protein (probable) In-silico None [ 195 , 219 ] Drugs acting on cytokine release Azithromycin Not conclusive (Change in endosomal pH), cytokines Inhibits viral replication and IL-6 production In-vitro (host cells), humans NCT04381962 - Phase 3 NCT04332107 - Phase 3 NCT04334382 - Phase 3 [ 198 , 220 , 221 ] Doxycycline Cytokines Inhibits viral replication and IL-6 production Humans NCT04371952 - Phase 3 NCT04433078 - Phase 2 IRCT20200418047121N1- Phase 3 [ 198 ] Tocilizumab IL-6 receptor Inhibits IL-6 release Humans NCT04356937 - Phase 3 NCT04445272 - Phase 2 NCT04403685 - Phase 3 [ 33 , 164 , 169 ] Auranofin Viral RNA Inhibits viral RNA and Cytokines In-vitro None [ 182 ] Ruxolitinib Janus-kinase 1/2 Inhibits cytokine storm In silico, humans NCT04414098 - Phase 2 NCT04338958 - Phase 2 NCT04362137 - Phase 3 [ 188 , 222 , 223 ] Baricitinib Janus-kinase 1/2 Inhibits cytokine storm In silico, humans NCT04421027 - Phase 3 NCT04358614 - Phase 3 NCT04373044 - Phase 2 [ 189 , 222 , 224 ] Dexamethasone Inflammatory cells Inhibits release of cytokines In silico, humans NCT04325061 - Phase 4 NCT04395105 - Phase 3 NCT04347980 - Phase 3 [ 191 , 192 , 225 ] Miscellaneous Ivermectin Nuclear transport inhibitory activity (probable) Reduced viral RNA In-silico, in-vitro, humans IRCT20200408046987N1- Phase 3 NCT04390022 - Phase 2 NCT04381884 - Phase 2 [ 180 , 226 , 227 ] Pegylated IFNα-2b B cells through host interferon receptor, IFNAR1 signalling Enhanced immune response against viral infections Humans NCT04349410 - Phase 3 NCT04273581 - Phase 2 NCT04251871 [ 88 ] Statins Angiotensin converting enzyme 2 (Probable) Improve endothelial dysfunction Humans NCT04380402 - Phase 2 IRCT20190727044343N2- Phase 2–3 [ 136 , 152 , 155 ] Nitazoxanide Exactly not known Exactly not known In-vitro, humans NCT04423861 - Phase 2 NCT04359680 - Phase 3 NCT04406246 - Phase 4 [ 29 , 228 , 229 ]

COVID-19 pandemic

Human population of the twenty-first century is suffering a large-scale epidemic of highly pathogenic coronaviruses such as severe acute respiratory syndrome coronavirus (SARS-CoV) in 2002–03 [ 18 ], Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012 [ 19 ] and severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) in 2019–20. Coronaviruses are pleomorphic, enveloped, positive sense, 27–32 kb large RNA viruses with typical crown-shape glycoprotein spikes (peplomers) that cause respiratory and enteric diseases in humans and other animals [ 20 ]. Very high recombination rates lead to constant transcription errors and RNA-dependent RNA polymerase (RDRP) jumps in coronaviruses [ 21 ] give them a chance to develop into diverse zoonotic pathogens such as SARS-CoV2. SARS-CoV2 is a positive-sense single-stranded RNA virus classified as a strain of the species SARS-CoV, (genus beta-coronavirus; subgenus sarbecoronavirus; subfamily orthocoronavirinae; family coronaviridae) which earlier in 2002–03 caused an outbreak of SARS in Guangdong, China [ 22 ]. Overall genome sequence of SARS-CoV2 showed 79.5% similarity with SARS-CoV and interestingly, 96.2% similarity with bat coronavirus RaTG13, suggesting its origin from a bat virus [ 23 , 24 ]. Though not certain, yet it is suspected that the introduction of this new coronavirus to humans might have been facilitated by an intermediate host, the pangolins [ 25 ].

As per WHO report, a case of pneumonia of unknown causative pathology from Wuhan city of China was first time reported to the WHO Country Office on 31 December 2019. The outbreak of the coronavirus-associated acute respiratory disease throughout the world was named as COVID-19 and it was classified as 2019-nCoV (SARS-CoV2) [ 26 ]. The classification and naming of the virus were done by the Coronaviridae Study Group of the International Committee on Taxonomy of Viruses. Novel coronavirus genome sequencing by China was publicly available on the Global Initiative on Sharing All Influenza Data (GISAID) platform on 12 January 2020. First case of novel coronavirus outside of China was reported in Thailand on 13th January 2020 (WHO). The novel coronavirus outbreak was declared as Public Health Emergency of International Concern on 30 January 2020 (WHO). This disease has been given name as COVID-19 by the WHO on 11th February 2020. As on 11th March 2020, COVID-19 was recognized as a pandemic by the WHO and there have been around 18,354,342 cases and 696,147 deaths reported due to COVID-19 upto 5th August 2020. Till date as per WHO, there is no treatment available for the control of COVID-19. In the current scenario of lacking efficient and specific treatments for SARS-CoV2 infections and the urgent need to restrain the pandemic, drug re-tasking appears to be the most suitable tool to find out the best therapeutic option for COVID-19 [ 27 ].

The mechanisms of infection by the SARS-CoV2 are not clear yet, however, it is genetically similar to SARS-CoV and other coronaviruses [ 28 ]. Hence the common mode of pathogenicity is being explored for targets of treatment. The therapeutic targets depending on the common mode of pathogenicity can be classified as virus-related targets and host-related targets.

Repurposed drugs that act through virus-related targets such as RNA genome

Replication of SARS-CoV2 depends directly on the key enzyme RDRP. It is interesting to note that potential drug targets protease and polymerase for SARS-CoV2 and SARS-CoV are highly conserved with 96% and 97% overall identity. Therefore, blockers developed against the SARS may act as good therapeutic candidates to bind protease or polymerase sites against SARS-CoV2 (GISAID, 2020) (Fig. 1 ). Fig. 1 Therapeutic targets of the currently considered drugs for repurposing against COVID-19. 1. Coronaviruses suppress the antiviral immunity, hence maintaining an antiviral state with interferons. 2. Virus enters the cell by fusion of the viral spike proteins with cellular ACE2 receptor, followed by ACE2 downregulation. Angiotensin receptor blockers (ARBs), Angiotensin-converting enzyme inhibitors (ACEIs) and statins increase ACE2 expression, hence may have efficacy in this condition. 3. Fusion is followed by endocytosis of the virus, where low endosomal pH helps in lysis of the viral structural proteins. Disruption of this acidic environment by diprotic bases like chloroquine and hydroxychloroquine may produce an antiviral effect. 4, 5. Release of nucleic acid (NA) into the cytoplasm and translation of the viral proteins using host ribosomes, 6. Proteolysis by viral main protease enzyme makes functional proteins e.g. RNA dependent RNA polymerase (RDRP). Thus, inhibition of the main protease enzyme by inhibitors like lopinavir, ritonavir and darunavir, may have efficacy against the virus. 7. RDRP is essential for replication and transcription of the virus. RDRP inhibitors, remdesivir, favipiravir, ribavirin and arbidol may be effective against coronaviruses. 7, 8. Subsequent translation and proteolysis into structural proteins followed by packaging makes intact virions, which get exocytosed (9) from the cell

Remdesivir

On the basis of current knowledge about the use of remdesivir in SARS-CoV2 infection, remdesivir is considered as the potential drug candidate for repurposing against the COVID-19. Remdesivir (GS-5734) is a nucleoside analog originally developed against Ebola viruses by Gilead Sciences Inc, a USA based Biopharmaceutical Company (Table 2 ). Though the drug failed to show effect against Ebola, the preliminary results from in-vitro and in-vivo preclinical studies as well as case reports indicate its efficacy against SARS-CoV2. Recently, in Vero E6 cells, remdesivir has been shown to block the viral infection at low concentration (EC 50 = 0.77 μM) with high selectivity index (SI > 129.87). The EC 90 value (1.76 µM) was also low enough to be achieved in non-human primate models [ 29 ]. It also efficiently inhibited SARS-CoV2 infection in human liver cancer Huh-7 cells [ 23 ]. In Rhesus macaques, the drug showed therapeutic and prophylactic efficacy against both SARS and MERS coronaviruses, indicating its potential against diverse coronaviruses including SARS-CoV2 [ 30 ]. Similarly, in a Ces1c-knockout mouse model of SARS-CoV infection, remdesivir in both prophylactic and therapeutic use significantly reduced lung viral titers, though the survival and lung pathology were not improved [ 31 ]. Treatment with intravenous remdesivir on day 7 of hospital admission, clearly improved the clinical condition from the next day in a 35-year-old COVID-19 patient in Washington, USA [ 32 ]. In Italy, remdesivir has been used (200 mg every 12 h as a loading dose followed 100 mg every 12 h for 10 days thorough intravenous route) with other supportive therapy in the clinical management of COVID-19 patients presented with a range of modified early warning score (MEWS) from less than 3 to more than 4 [ 33 ]. In a recent report, clinical improvement in 36 of 53 patients (68%) of severe COVID-19 patients has been observed with the compassionate-use of remdesivir in a cohort study [ 34 ]. According to another study remdesivir was superior over the placebo in shortening the time to recovery in adult patients hospitalized with COVID-19. In the trial that was conducted at 60 sites and 13 subsites in different parts of the world, mortality rate was 7.1% with remdesivir and 11.9% with placebo by 14 days in 1059 patients in which 538 were in remdesivir group and 521 were in the placebo group [ 35 ]. Another trial, however, suggests differently, that remdesivir has no such statistically significant clinical benefits, although, patients who were administered with remdesivir showed a faster clinical improvement in numerical terms, with symptom duration of 10 days or less in a study of 237 patients in which 158 patients received remdesivir and 79 (one withdrew) were on placebo in a randomised, double-blind, placebo-controlled, multicentre trial at ten hospitals in Hubei, China [ 36 ]. Another clinical trial done with remdesivir in severe COVID-19 patients without mechanical ventilation support indicated no significant difference between 5-day and 10-day course of remdesivir therapy, however, by day 14, a clinical improvement was noticed in 64% of patients in the 5-day group and in 54% in the 10-day group at 2 points or more on the ordinal scale out of 7-point ordinal scale [ 37 ]. Table 2 Chemical structure of pharmacological agents reviewed

Being a nucleotide (adenosine) analog, remdesivir gets incorporated into the replicating genome of the virus after being converted into its triphosphate form. The triphosphate forms compete with adenosine triphosphate (ATP) to act as a substrate of RDRP and have been found to cause significantly efficient incorporation as compared to ATP. Remdesivir adds three more nucleotides before terminating the growing RNA chain [ 38 ]. The extra three nucleotides may protect the inhibitor from removal by the viral 3′–5′ exonuclease activity [ 39 ], contributing to the lack of acquiring resistance.

The pharmacokinetics, metabolism and distribution of remdesivir have been studied in non-human primates, previously. In rhesus monkeys, 10 mg/kg dose yields a half life ( t 1/2 ) of 0.39 h with fast systemic elimination. The active metabolite of remdesivir, 1′-cyano-substituted adenine C-nucleoside ribose analogue (Nuc) then appears which produces antiviral activity [ 40 ]. However, the drug is parenterally administered through intravenous route and is not expected to be given to mildly infected patients, though potent action is expected in mild infection. It is under clinical trial in China and USA against COVID-19 by 15th of April, 2020 ( NCT04252664 and NCT04257656 ). However, seven clinical trials are underway on remdesivir to evaluate its efficacy on SARS-CoV2 infection ( https://www.gilead.com/purpose/advancing-global-health/covid-19/remdesivir-clinical-trials ). The results of NCT04257656 clinical trial showed that intravenous remdesivir was adequately tolerated by COVID-19 patients [ 36 ]. In the third trial ( NCT04292899 ) with the severely infected COVID-19 patients, with the use of remdesivir, common adverse effects were observed such as nausea, acute respiratory failure, increased alanine aminotransferase (ALT) and constipation [ 37 ]. In all these studies ramdesivir was administered intravenously as 200 mg SID on day 1 and followed by 100 mg SID for the subsequent period.

Favipiravir

As per the information obtained from the Chinese news channel by Dong and Co-workers, this drug got an approval against the SARS-CoV2 infected patients in China on 15th February, 2020 since it had drastically attenuated the illness of the SARS-CoV2 infected patients [ 41 ]. Favipiravir (6-fluoro-3-hydroxy-2-pyrazinecarboxamide, T-705 also marketed as AVIGAN) was developed by a Japanese firm, Toyama Chemical Co., Ltd. and has been approved in Japan for Influenza since 2014 (Table 2 ). The drug effectively inhibits the enzyme RDRP. In Vero E6 cells this drug showed an EC 50 of 61.88 µM and selectivity index of more than 6.46 against SARS-CoV2 [ 29 ]. Though this concentration against SARS-CoV2 is very high, the drug may be tested in an animal model based on its performance against Ebola virus. Remarkably this drug had shown 100% efficacy against Ebola in a mice model although it had a very high EC 50 in Vero cells [ 42 ]. Randomized trials are being conducted for this drug in combination with other drugs against coronaviruses (Favipiravir + interferon-α, ChiCTR2000029600, favipiravir + baloxavir, ChiCTR2000029544).

Favipiravir is a nucleoside precursor which inhibits the broad range of influenza virus strains, however, it shows antiviral activity through its NTP form (converted into an active phosphoribosylated form, T-705 RTP) via direct inhibition of the RDRP activity of influenza A virus polymerase and it has also shown lethal mutations within the viral genome [ 43 ]. Nevertheless, the exact mode of action, precise molecular mechanism and its interaction between the nucleotide and the viral polymerase could be investigated in the SARS-CoV2 infection.

Favipiravir exerts its antiviral action in a dose-dependent manner [ 44 ]. Its oral bioavailability is close to 100% and has a short half life of 2–5.5 h [ 45 , 46 ]. In Humans, the plasma protein binding of favipiravir is 54%. Favipiravir undergoes metabolism in the liver mainly by aldehyde oxidase (AO) and partially by xanthine oxidase (XO) and the inactive oxidative metabolite (T-705 M1) is excreted by kidneys. A study reported that in Pichindé arenavirus infection the kinetics of absorption, elimination and time to maximum drug concentration is altered. The T-705 M1 levels were higher in the infected animals [ 47 ]. Further, favipiravir concentration may be increased by drugs those undergo metabolism through AO such as raloxifene, tamoxifen, estradiol, cimetidine, felodipine, amlodipine, verapamil, propafenone, amitriptyline, zaleplon, citalopram, sulindac and famciclovir. Concomitant administration of acetaminophen and favipiravir showed increased area under curve (AUC) of former drug possibly due to inhibition of the sulfate transferase by the latter drug [ 46 ].

The drug did not show any toxicity at the oral dose of 500 mg/kg/day for 10 days in guinea pigs [ 48 ]. This can be converted to 108 mg/kg of human equivalent dose [ 49 ] which is far greater than the dose prescribed for COVID-19 on first day i.e. 53 mg/kg/day (1600 mg BID on the first day) ( https://www.clinicaltrialsarena.com/comment/influenza-favipiravir-covid-19/ ). However, use of this drug may be approved with the availability of more number of clinical results.

Ribavirin

Ribavirin, a broad-spectrum antiviral drug, is a guanosine analog approved for treating hepatitis C virus in combination, and respiratory syncytial virus as monotherapy. Effect of this drug has been assessed in patients with SARS [ 50 ] and MERS [ 51 ] (Table 2 ). Against SARS-CoV2, it has very high EC 50 of 109.50 μM and selectivity index more than 3.65 in Vero cells. Ribavirin in its monophosphate form inhibits host inosine monophosphate dehydrogenase (IMPDH) enzyme that controls intracellular guanosine triphosphate (GTP) pools [ 52 ]. Exhaustion of intracellular GTP pool indirectly inhibits viral RDRP enzyme. It also interferes with mRNA capping. Ribavirin at a dose rate of 500 mg 2–3 times/day in combination with other drugs such as lopinavir/ritonavir or interferon (IFN)-α through intravenous route for not more than 10 days made the SARS-CoV2 infected patients more resistant to respiratory distress syndrome as well as death [ 41 ].

The oral bioavailability of ribavirin is 52%, which is due to modest first-pass metabolism in liver [ 53 ]. Estimated half-life is 3.7 h [ 54 ]. Ribavirin-induced hemolytic anemia is a most commonly reported adverse effect and frequently it requires dose reduction [ 55 ]. Further, close monitoring of renal impairment in terms of creatinine clearance during therapy is required. Old age, decreased renal function, low body weight and female gender are other risk factors to be considered during ribavirin therapy [ 56 , 57 ].

Animal studies have shown teratogenic potential of ribavirin. Therefore, exposure during pregnancy should be avoided. Other less common yet pertinent adverse effects are bronchospasm and pulmonary edema on inhalation [ 43 , 57 ]. Neutropenia, thrombocytopenia, skin rashes, anorexia and depression are some minor adverse effects of ribavirin that need to be monitored in the sensitive patients [ 58 ]. In a recent clinical trial with combinations of ribavirin + interferon-alpha, lopinavir/ritonavir + interferon-alpha and ribavirin + lopinavir/ritonavir + interferon-alpha in patients with mild to moderate COVID-19 showed that ribavirin plus lopinavir/ritonavir combination showed a significant increase in gastrointestinal adverse effects [ 59 ].

Repurposed drugs acting through polypeptide packing

The viral RNAs get translated into polypeptide chains which get cleaved into functional proteins before packing into virions. The viral main proteases are responsible for the cleavage of these polypeptide chains [ 60 ]. SARS-CoV2 protease has 96% overall similarity with SARS-CoV [ 61 ]. Protease inhibitors used in HIV-1 therapy are shown to be effective against SARS-CoV [ 62 ]. In-silico and in-vitro approaches have been used to validate the inhibition of SARS-CoV2 protease by HIV-1 protease inhibitors [ 63 , 64 ]. Numerous protease inhibitors are approved by FDA for use in HIV therapy. The agents available from this class include saquinavir, amprenavir, indinavir, nelfinavir, ritonavir, and lopinavir. Few of them are being considered against SARS-CoV2 (Fig. 1 ).

Lopinavir-ritonavir combination

This drug combination is available under brand name Kaletra and was developed by Abbott Laboratories, USA. This drug was approved by FDA in the year 2000 as an anti-retroviral for the treatment of HIV patients. Lopinavir is rapidly degraded in the human body by the host proteases, hence is given with ritonavir (another protease inhibitor) at a lower dose, which helps lopinavir remain active for a longer time by inhibiting the metabolizing enzyme cytochrome P450 [ 65 ] (Table 2 ).

Coronavirus main proteases are cysteine proteases whereas HIV main proteases are aspartic proteases. Nonspecific protease inhibition by protease inhibitors used in HIV therapy has been found effective against SARS-CoV. Lopinavir has comparable binding energies against the SARS-CoV2 and HIV-1 proteases [ 66 ]. In SARS-CoV2 patients treated with lopinavir-ritonavir, a significant virus clearance has been achieved [ 67 , 68 ]. A 47-year old patient, who failed to respond to methylprednisolone and interferon therapy, got quick improvement with additional lopinavir and ritonavir tablets therapy [ 69 ]. In 36 paediatric patients between the age of 0–16 years with confirmed COVID-19 from three hospitals in Zhejiang, China, use of lopinavir-ritonavir (syrup twice a day) along with interferon α to 14 patients (6 patients needed oxygen inhalation but not sure whether it included lopinavir-ritonavir group) showed a mean of hospital stay time of 14 days and all were cured [ 70 ]. Based on these initial successful reports, SARS-CoV2 main protease has been docked for 1. 3 billion protease inhibitor compounds [ 71 ]. Also, lopinavir-ritonavir has been included in SOLIDARITY trial ( NCT04330690 ).

However, in a recent clinical trial with 199 severely ill patients with confirmed SARS-CoV2 infections, lopinavir-ritonavir treatment did not improve the time to clinical improvement and mortality rate beyond standard care and further, some patients also showed adverse drug effects such as gastrointestinal disturbances [ 72 ]. In a study on four COVID-19 patients treated with Western (lopinavir 400 mg/ritonavir in a ratio of 400 mg to 100 mg for q12 h through oral route), arbidol (0.2 g, three times in a day through oral route), and Chinese traditional medicine Shufeng Jiedu capsule (SFJDC, 2.08 g, three times in a day through oral route) combination for 6–15 days, it has been observed that out of the two mild and two severe SARS-CoV2-infected pneumonic patients, three patients showed significant improvement in pneumonia associated symptoms and the remaining patient with severe pneumonia has also shown signs of improvement till the date of reporting [ 73 ].

Most HIV protease inhibitors show poor bioavailability. They are extensively metabolized by microsomal CYP3A4 enzymes. Other agents that induce or inhibit these metabolizing enzymes influence their effectiveness. Side effects associated with the use of protease inhibitors include diarrhea, vomiting, diabetes, hypertriglyceridemia, and hypercholesterolemia. It also could cause severe hepatic damage [ 74 ]. Therefore, a lot of clinical and experimental study regarding the use of lopinavir-ritonavir is required to reach a conclusive statement.

The most common adverse effect of ritonavir/lopinavir is diarrhea and gastrointestinal disturbance. Elevated liver enzymes, dyslipidemia, asthenia, headache and skin rashes are some minor side effects [ 75 – 77 ]. Ritonavir/lopinavir co-administration causes mild hepatotoxicity (elevated alanine aminotransferase, ALT) [ 78 ]. However, sole use of ritonavir at a higher dose (600 mg/BID) may increase the risk of severe hepatotoxicity [ 79 ]. A rarely observed adverse effect with ritonavir is retinal pigment epitheliopathy. The risk factors for the retinopathy are high dose and hepatic impairment [ 80 ].

Darunavir

Darunavir is a second-generation non-peptide protease inhibitor effective against HIV-1. It has a distinct chemical structure that enhances binding affinity and reduces dissociation rate, making it more potent than the other protease inhibitors [ 81 ] (Table 2 ). Using computational drug design methods, darunavir was identified as one of the promising hits for inhibition of chymotrypsin-like protease of SARS-CoV2 [ 82 ]. Results of a structural analysis showed no binding of darunavir to SARS-CoV2 protease ( https://www.eacsociety.org/home/covid-19-and-hiv.html ). Anyhow, recently in Shanghai, in-silico and an enzyme activity test based drug screening revealed 30 agents with potential antiviral activity against SARS-CoV2 including darunavir ( https://www.simm.ac.cn/xwzx/kydt/202001/t20200125_5494417.html ). Interestingly, therapeutic doses of darunavir are reported to be too low to cause cytotoxic effects, affording a wide margin of safety [ 81 ]. In an in-vitro study, darunavir at 300 micromolar concentration was found to inhibit SARS-CoV2 virus replication by 280 times in comparison to the untreated group ( https://www.sd.chinanews.com/2/2020/0205/70145.html ). Further, darunavir has been used (600 mg tablet every 12 h) along with other anti-viral drugs and supportive therapy in the clinical management of COVID-19 patients presented with a range of MEWS from less than 3 to more than 4 in Italy [ 33 ].

Darunavir is rapidly absorbed after oral administration and has a terminal elimination half-life of 15 h. Approximately 95% of the drug is plasma protein bound and metabolized exclusively by CYP3A4. Therefore, co-administration of small doses of ritonavir (CYP3A4 inhibitor) increases the bioavailability of darunavir. Combination therapy with other CYP3A4 inhibitors (e.g. statins) with darunavir/ritonavir requires caution or is even contraindicated [ 83 , 84 ].

A recent study correlated the daurnavir use with increased risk of myocardial infarction in HIV patients and concludes that cardiovascular disease (CVD) risk increases with darunavir exposure. Therefore, it may be used cautiously in patients with underlying cardiac diseases [ 85 ]. Before, regular use of this drug, more pharmacological profile may further be investigated during the use in COVID-19 patients.

Repurposed drugs acting through host targets such as antiviral immunity

The pattern recognition receptors in immune cells recognize the viral pathogen-associated molecular pattern (PAMPs) to stimulate antiviral interferon responses in the host [ 86 ]. The secreted interferons activate hundreds of interferon-stimulated genes which encode proteins with profound effects against the virus (Fig. 1 ).

Interferons (pegylated IFNα-2a and pegylated IFNα-2b)

The interferons (IFNs) are antiviral molecules classified into type I (IFNα, IFNβ, IFNω, and IFNτ) and type II (IFNγ). IFNα plays a critical role in innate immunity against viral infection which prompts its use in the treatment of many clinical viral infections. The recombinant IFNα is interferon alfacon-1. The pegylated types are pegylated IFNα-2a and pegylated IFNα-2b [ 87 ]. Pegylated interferon alfa-2b acts to target B cells through host interferon receptor, IFNAR1 signalling and enhances immune response against viral infections [ 88 ]. Recombinant human IFNα-2b has been shown to possess wide antiviral spectrum, low toxicity and high therapeutic index in vitro. Quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) results revealed anti-viral effect of recombinant human IFNα-2b on respiratory viruses such as influenza B virus, parainfluenza virus, respiratory syncytial virus and coronavirus which was stronger in comparison to the effect of ribavirin [ 89 ]. In another study, IFNα-2b administered by nasal spray reduced positive rates of immunoglobulin M (IgM) antibody against all four respiratory viruses (parainfluenza virus, influenza B, adenovirus and respiratory syncytial virus) possibly suggesting the lower virus titre due to IFNα-2b [ 90 ]. In the rhesus macaque, IFNα-2b with ribavirin showed very good effect against beta-coronavirus emerged in Saudi [ 91 ], however, was unsatisfactory in humans [ 92 ]. In China, intranasal IFNα (5 × 10 6 U) twice a day in combination with ribavirin is one of the guidelines for the treatment of COVID-19 patients [ 41 , 93 ]. It was further showed that the infection rate of SARS-CoV2 was decreased by IFNα-2b sprays [ 94 ]. IFNα-2b has demonstrated potent anti-viral activities against respiratory viruses and may serve for the prevention and treatment of SARS-CoV2 as well. Nevertheless, thorough evaluation in appropriately designed randomized trials is recommended before forging on.

PEG-IFNα-2b is a linear 12 kDa molecule and susceptible to hydrolysis. It is absorbed quickly and distributed widely. After administration PEG-IFNα-2b gets hydrolysed and the free IFN α -2b circulates in the body. Most of the free IFN α -2b excreted solely through kidneys. Therefore, it requires dose adjustment in patients with renal impairment. Further, the clearance of PEG-IFNα-2b decreases after repeated dosing. Therefore, it is administered according to body weight. Conversely, the PEG-IFNα -2a is a 40 kDA branched chain molecule which is absorbed more slowly and has poor tissue distribution. PEG-IFN α -2a has long half-life. Therefore, it is used at a fixed dose of 180 μg per week for the treatment of hepatitis C virus infection. PEG-IFNα-2a is metabolized by both the kidneys and liver, therefore this drug does not require a major dose modification [ 95 ].

Number of adverse events was recorded with PEG-IFN α therapy. Dizziness, headache, depression, fatigue, insomnia, alopecia, myalgia, arthralgia, pyrexia, anorexia are the most common constitutional symptoms observed with PEG-IFN α -2a and PEG-IFN α -2b therapy in various other diseases. Hematologic adverse events such as leucopoenia, thrombocytopenia and myelosuppression, thyroid disease, lung disease and retinopathy are the other adverse events recorded in the patients receiving PEG-IFN α- 2a/PEG-IFN α -2b [ 96 – 98 ]. Dose limiting, mild injection site reactions/inflammations were observed commonly in PEG-IFN α -2b therapy [ 96 ]. Most of the adverse events are well tolerated and become less severe during the progression of therapy. The neuropsychiatric adverse effects were observed in patients undergoing interferon-α therapy and may require timely medical interventions [ 99 ]. In the case of severe events, discontinuation and dose reduction will help to overcome these adverse events [ 96 ].

Lopinavir-ritonavir and interferon-β combination

Lopinavir-ritonavir along with interferon beta is undergoing clinical trial (MIRACLE) against MERS in Saudi Arabia wherein a total of 76 patients have enrolled till Jan 2020 [ 100 ]. Interferons are the antiviral weapons of the body and coronaviruses are known to reduce the host antiviral immunity by suppressing the production of interferons. So, replacement therapy with interferons or interferon inducers has the potential to reduce the viral load in the body. They augment the host response to the viral infection. Lopinavir-Ritonavir-Interferon-β1b treatment improved the clinical findings and lowered the lung viral load in MERS-affected common marmosets [ 101 ]. Results of a recent clinical trial ( NCT04276688 ) on COVID-19 patients showed the safety and efficacy of this combination. Adverse events like self-limited nausea and diarrhoea were recorded in this study. However, there was no significant difference in the adverse effects between the combination group and ritonovir/lopinavir alone (control group) [ 102 ].

Repurposed drugs targeting the virus uptake pathways

The coronaviruses enter the cell by two ways, (1) endocytosis, virus is taken up into the cell along with the endosomes, (2) fusion of the viral spike protein with the cell surface receptor ACE2 [ 103 ], the latter being the predominant pathway of virus entry [ 104 ]. Blockade of entry pathways may be effective targets for treatment (Fig. 1 ).

Chloroquine and hydroxychloroquine

Chloroquine, primarily known for its anti-plasmodium actions, has antiviral activity as well. This drug originally derived from Cinchona plant is now largely a synthetic drug (4-amino quinoline) discovered by Bayer Laboratories. Chloroquine and its analogs are potent inhibitors of most coronaviruses [ 105 ] (Table 2 ).

Chloroquine and hydroxychloroquine are weak diprotic bases. These drugs take a similar pathway like the virus and concentrate in the endosomes increasing the pH of the endosomal fluid. The acidic pH of the endosomes is necessary for the optimal activity of viral enzymes responsible for proteolysis and post-translational modification of nascent proteins. Disruption of acidic pH thus blocks the replication and lifecycle of the virus [ 106 ]. In addition, the drug is known to interfere with the glycosylation of the host receptor for the virus, ACE2. Faulty terminal glycosylation may affect the binding and subsequent entry of the virus into host cells [ 107 ].

Cell culture studies in African green monkey Vero E6 cells indicate significantly higher potency for chloroquine compared to hydroxychloroquine [ 108 ]. Chloroquine has EC 90 value of 6.90 μM against the SARS-CoV2 in Vero E6 cells, which can be clinically achievable after administration of 500 mg as shown in rheumatoid arthritis patients [ 109 ]. A safe dosage of 6–6.5 mg/kg per day of hydroxychloroquine could yield serum levels of 1.4–1.5 μM in humans [ 110 ]. It is speculated that with a safe dosage, hydroxychloroquine could achieve concentration in the above tissues to inhibit SARS-CoV2 infection. Hydroxychloroquine phosphate (400 mg tablet every 12 h as a loading dose followed 200 mg tablet every 12 h for 10 days) or chloroquine phosphate (250 mg of two tablet every 12 h for 10 days) along with other anti-viral drugs and supportive therapy have been used in the clinical management of COVID-19 patients presented with a range of MEWS from less than 3 to more than 4 in Italy [ 33 ]. Chloroquine and hydroxychloroquine have been considered for SOLIDARITY trial ( NCT04330690 ). Hydroxychloroquine has shown side effects such as prolonged QT interval and heart failure, though controversy exists. Recently, WHO stopped hydroxychloroquine arm of the Solidarity Trial to find an effective COVID-19 treatment. This recommendation was developed on the basis of data obtained from Solidarity trial (including the French Discovery trial data and UK's Recovery trial data). These trials showed that hydroxychloroquine did not result in the reduction of mortality of COVID-19 patients who were hospitalized when compared with standard care (briefed on 17 June 2020 by WHO).

Use of chloroquine for SARS-CoV2 asks for a high dose but an overdose of chloroquine has been reported to cause poisoning and death [ 111 ]. In comparison, hydroxychloroquine is safer with 40% less toxicity in animals [ 112 ]. Oral absorption of chloroquine and hydroxychloroquine in humans is efficient. Both the drugs distribute similarly in different tissues with high concentrations in the liver, kidney, lungs and spleen [ 113 ].

Chloroquine is two to three times as toxic in animals as hydroxychloroquine [ 112 ]. The acute toxicity of chloroquine causes death due to cardiac and respiratory arrest [ 111 ]. Adverse effects of chloroquine/hydroxychloroquine therapy at the therapeutic doses include retinopathy, myopathy, electrocardiographic changes, bleaching of hair, pruritus, headaches, dizziness and gastrointestinal upset [ 114 – 116 ]. Hydroxychloroquine retinal toxicity in the patients is far more common in patients taking this drug for greater than 5 years with the overall prevalence of 7.5% [ 117 ]. A study showed even with the recommended therapeutic dose of hydroxychloroquine produced bilateral maculopathy and it was attributed to the differential susceptibility of the retinal epithelium to hydroxychloroquine [ 118 ].

Hydroxychloroquine and chloroquine are orally well absorbed and show 70–80% oral bioavailability. Chloroquine is 60% bound to plasma proteins and distributed extensively. Following administration, chloroquine is rapidly dealkylated to pharmacologically active desethylchloroquine and bisdesethylchloroquine. Metabolism of hydroxychloroquine is similar to chloroquine except for a third metabolite desethylhydroxychloroquine which is also produced during metabolism. Both hydroxychloroquine and chloroquine have prolonged half-lives, between 40 and 50 days, and low blood clearance by kidneys and liver. For both chloroquine and hydroxychloroquine, approximately 40–60% is excreted as an unchanged or metabolized drug through the kidneys, 8–25% is excreted in an unchanged or changed form in the feces, 5% is sloughed off through the skin, and 25–45% is stored long term in lean body tissues [ 119 – 122 ].

Hydroxychloroquine should be cautiously used in patients with known hepatic or renal dysfunction. The co-administered drugs with hydroxychloroquine excreted via liver/kidney may interact with hydroxychloroquine and modulates its pharmacokinetics and toxicity. Hydroxychloroquine has been reported to cause severe hypoglycaemia when co-administered with oral hypoglycaemic drugs. There have been few reports of mild to severe hepatic failure in patients with hydroxychloroquine treatment [ 117 ]. Racial difference in toxicity has also been reported wherein the incidence of pericentral maculopathy was common in Asian (50%) than Caucasian (2%) patients [ 123 ]. Further, the use of chloroquine and hydroxychloroquine may be warranted in prophylaxis strategy as well as in COVID-19 patients with more number of clinical trials.

Arbidol

Arbidol, an indole-derivative, also known as umifenovir is a potent broad-spectrum antiviral agent. This drug has shown activity against a wide range of enveloped and non-enveloped viruses [ 124 ] (Table 2 ). It is effective against numerous pathogenic respiratory viruses and relatively very safe for use [ 125 , 126 ]. Arbidol is an approved therapeutic agent against influenza in Russia and China [ 127 ]. Arbidol and arbidol mesylate were reported to act directly on viral replication of SARS-CoV at an early stage in vitro [ 128 , 129 ]. The anti-viral mechanism of arbidol against influenza A and B involves viral fusion inhibition by hindering the hemagglutinin fusion machinery with the membrane, thus blocks virus entry into the cell [ 127 ]. Arbidol is one of the drugs in clinical trial phase 4 for pharmaceutical interventions of COVID-19 and treatment of COVID-19 patients with arbidol leads to a reduction in the mortality rate and increase in the recovery rate [ 130 , 131 ]. Arbidol treatment coupled with lopinavir/ritonavir reckoned to retard the development of pulmonary lesions concurrently reducing the respiratory and gastrointestinal COVID-19 viral load thus lowering the transmission [ 132 ]. Encouragingly, seasonal prophylaxis with arbidol reduced influenza morbidity in patients with asthma and COPD during epidemic [ 133 ]. Four cases with mild to severe SARS-CoV2 pulmonary symptoms were subjected to antiviral therapy consisting of arbidol, lopinavir/ritonavir, and Shufeng Jiedu (traditional Chinese medicine) along with supportive care. Following medication, three patients showed a notable reduction in pneumonia-related manifestations and two of them were discharged after testing negative for SARS-CoV2 [ 73 ]. In COVID-19 patients, reduction in fever and cough; improvement in chest computed tomography (CT) and clinical status among the arbidol, lopinavir/ritonavir and control group remained statistically indifferent. However, arbidol was better tolerated by patients whereas test subjects administered with lopinavir/ritonavir experienced adverse events during the follow-up period [ 134 ].

The half-life of arbidol is between 17 and 21 h and 40% of the total drug excreted unchanged in feces. Arbdiol conjugation with glucuronide and sulfonation is evident. The major Phase I enzyme involved in its metabolism was CYP3A4, therefore, a possible interaction with CYP3A4 inducers/inhibitors may happen [ 135 ].

The drug has oral lethal dose (LD50s) of 340–400 mg/kg in mice, and > 3000 mg/kg in rats and guinea pigs. Intravenous LD50s are 109 mg/kg in mice and 140 mg/kg in rats. In long term animal studies, it showed no adverse effects with 10–50 times of human dose and no developmental toxicities were observed [ 127 ].

Angiotensin receptor blockers

It has been noticed that SARS-CoV2 binds the ACE2 receptors similar to the SARS coronavirus [ 23 ]. COVID-19 is associated with the acute respiratory distress syndrome (ARDS) and higher activity of ACE2 leads to attenuation in ARDS [ 136 , 137 ]. ACE2 expression is downregulated in COVID-19 patients [ 138 ]. It is a general observation throughout the world that aged persons affected with COVID-19 suffer from high mortality. Association between COVID-19 infection and the process of chronological aging has been understood with the presence of two host receptors CD26 and ACE2 which are associated with senescence. The major pathway of virus entry into the host in case of SARS-CoV and SARS-CoV2 is through the target cell ACE2. Spike proteins of the virus attach to the cell surface ACE2 expressed in epithelial cells of the oral mucosa, lungs, intestine, blood vessels and kidney.

Angiotensin receptor blockers (ARBs) which inhibit the action of ACE, an isoform of ACE2, are known to increase the expression of ACE2 [ 139 ] (Fig. 1 ; Table 2 ). The patients with diabetes and cardiovascular diseases regularly take ACE inhibitors and ARBs. Hence, they remain under continuous risk of SARS-CoV2 infection. However, experimental studies with ARDS indicate a higher level of ACE2 reduces the severity of the disease [ 137 ]. Increased ACE2/ACE ratio may improve the host response to viral infection by correcting the endothelial dysfunction common to most viral infections [ 140 ]. Experimental and clinical studies are needed urgently on this aspect for repurposing of commonly used ARBs or ACE inhibitors (ACEIs). ARBs are well-tolerated drugs with minimal side effects in the population. However, a lot of patients from South America, Central America and Spain, had stopped or intended to interrupt their treatments with anti-hypertensive drugs like ACEIs such as enalapril or ARBs such as losartan fearing the risk of SARS-CoV2 infection [ 141 ]. However, another school of thought provided alternative suggestions about the use of renin–angiotensin–aldosterone system (RAAS) inhibitors. They suggested that though ACE2 expression may be enhanced with the use of RAAS inhibitors, sudden withdrawal of these drugs may be responsible for higher risk in patients of COVID-19 already affected with cardiovascular illnesses. Therefore, the use of RAAS inhibitors should continue in patients with COVID-19 under continuous observation [ 138 , 142 ]. Out of 42 COVID-19 patients taking antihypertensive drugs, 17 patients who were treated with ACEIs/ARBs showed less mortality in comparison to patients taking drugs other than ACEIs/ARBs in Shenzhen Third People’s Hospital, China [ 143 ]. ACEIs and ARBs may improve the clinical condition of the COVID-19 patients in a clinical setting by maintaining a low level of IL-6 level in peripheral blood and through increment in a cluster of differentiation CD3 and CD8 T cell counts in peripheral blood and decreased the peak viral load [ 143 ]. Contrary to the previous report, another retrospective study from the Union Hospital of Wuhan, China done on 112 patients suggested that ACEI/ARBs medication has no difference in the critical group and general group and further, did not show any effect on the morbidity and mortality of COVID-19 patients associated with cardiovascular diseases [ 144 ]. It is reported that ACE inhibits the formation of Ang II in the presence of ACEIs; therefore, these prevent the negative effects induced due to AT1R as well as positive effects derived from the Ang II binding with AT2R and further, its transformation into Ang-(1–7) [ 145 ]. Therefore, it could be assumed that the use of ACEIs leads to the protective effects in the lung in COVID-19 patients.

Angiotensin receptor blockers are the most commonly used drugs for hypertension and related cardiac problems. In general, ACEIs and ARBs have few interactions with ritonavir [ 146 , 147 ]. Generally, ARBs are well tolerated and the frequency of adverse reactions is less than 2%. There are no specific considerations for use in patients with hepatic and renal impairment [ 148 ]. ARBs are structurally related to losartan (except eprosartan) but the individual members exhibit diverse pharmacokinetic properties. Their bioavailabilities vary from 13–60% and half-lives are between 2 and 24 h. They are highly plasma protein bound (90–100%) and mostly metabolized and eliminated by the liver and, therefore, can be safely used in mild to moderate renal failure without any dose adjustment. However, losartan should be started with a lower dose in hepatic impairment and telmisartan should be avoided in case of renal impairment and congestive heart failure/digoxin therapy [ 149 , 150 ].

Statins

Statins, the lipid-lowering drugs, have shown pleiotropic activity through anti-inflammatory and immunomodulatory properties to prevent acute lung injury in different experimental and clinical conditions; therefore, it may be used as re-tasking drug for the COVID-19 patients [ 151 ] (Table 2 ). Statins are commonly taken for a lifetime to prevent coronary artery diseases. Studies have reported that these drugs increase the ACE2 expression [ 152 ]. ACE2 cleaves Ang II, a peptide which promotes endothelial dysfunction and cardiovascular diseases, and produces Ang-(1–7) which counters the effects of Ang II [ 153 ]. Stimulation of ACE2/angiotensin-(1–7)/Mas and angiopoietin/Tie-2 signaling axes help restoring viral infection-induced endothelial dysfunction and maintain the homeostasis of the patients [ 154 ]. ACE2 activity has shown to be up-regulated with the use of ARBs and atorvastatin [ 152 , 155 ] (Fig. 1 ). Statins being immunomodulatory have been hypothesized to work against MERS coronaviruses [ 156 ]. However, in animal models of SARS and MERS infections, reduced expression of the adapters, TIR-domain-containing adapter-inducing interferon-β (TRIF) or Myeloid differentiation primary response protein (MYD) 88 causes severe respiratory disease leading to death. Hence, the use of statins, which can further suppress MYD88 signaling, may exacerbate the disease condition [ 157 ].

Fungus derived statins (lovastatin, pravastatin and simvastatin) have elimination half-lives of 1–3 h and other synthetic compounds have elimination half-lives ranging from 1 h for fluvastatin to 19 h for rosuvastatin. Bioavailability of statins varies from 5–80% and 6–30% of the absorbed statins. Majority of satins are metabolized by the liver and the biliary excretion is the predominant route of excretion. Pravastaitn and rosuvastatin are excreted mostly unchanged by liver and kidneys. All statins are extensively bound to plasma proteins (> 90%) with the exception to pravastatin which is only 50% bound to plasma proteins [ 158 ].

Myopathy and rhabdomyolysis are the most frequent adverse effect of statins. Other common adverse effects include hepatotoxicity, peripheral neuropathy, cardiac toxicity, cognitive dysfunction, cataracts, diabetes mellitus and autoimmune necrotizing myopathy [ 159 , 160 ]. Most of the statins are CYP3A4 substrates and the inhibitors of this enzyme may increase blood levels of statins and therefore associated with adverse effects [ 161 ]. Statins have potential interactions with the protease inhibitor drugs and they are contraindicated in combination therapy [ 162 ]. USFDA warns using atorvastatin, lovastain, rosuvsatin, pravstatin, simvastatin with antiviral protease inhibitor drugs (For list please see https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-interactions-between-certain-hiv-or-hepatitis-c-drugs-and-cholesterol#dose ). In this case dose reduction and therapeutic drug monitoring will reduce the occurrence of adverse effects.

Drugs acting on host proinflammatory cytokines

Tocilizumab

Tocilizumab is a drug used against rheumatoid arthritis as well as cytokine release syndrome/systemic inflammatory response syndrome. This drug was introduced in Japan in the year 2008 and subsequently in the European Union (trade name RoActemra) in the year 2009. Later in the year 2010, it was used in the USA (Actemra) and this drug is an anti-human monoclonal antibody of the immunoglobulin G1k subclass [ 163 ]. This drug does not act on the virus but it acts to reduce the cytokine response of the host. Tocilizumab is a recombinant humanized monoclonal antibody which is responsible to bind the human IL-6 receptor and inhibiting its signal transduction pathway [ 164 ] (Fig. 1 ). A 60-year old man of Wuhan, China developed symptoms of chest tightness without fever and cough on 1st February 2020 and confirmed to be the first case of COVID-19 with multiple myeloma. The case was successfully treated with humanized anti–IL-6 receptor antibody, tocilizumab. The patient was administered 8 mg/kg tocilizumab through IV route for one time from day 9 to day 12 upon hospital admission and a decrease in IL-6 level was recorded, however, a rebound phenomenon of IL-6 level was observed, may be due to the recovery of the normal T cells and the patient was cured on day 19. The patient, however, had also received other therapies like 200 mg dose of umifenovir (arbidol) tablets orally for three times daily as antiviral treatment and 400 mg of moxifloxacin IV daily for three days [ 165 ]. However, in another 56 years old COVID-19 patient of end-stage renal disease (ESRD) in the USA treated with tocilizumab, hydroxychloroquine and broad spectrum antibiotics, the patient remained in critical condition throughout the study period [ 166 ]. A 57 years old woman from Switzerland suffering from systemic sclerosis (SSc) was on tocilizumab treatment for arthritis and SSc-associated interstitial lung disease (SSc-ILD) @ 8 mg/kg body weight every 4 weeks intravenously. On the basis of observation it has been reported that tocilizumab treatment given for chronic autoimmune diseases may prevent the development of severe COVID-19 [ 167 ]. A case of 42 years old patient with a respiratory failure linked to COVID-19 from France showed a rapid favourable outcome after two infusions of the tocilizumab at a dose rate of 8 mg/kg through intravenous route along with other therapy like lopinavir-ritonavir [ 168 ]. Tocilizumab treatment in 15 of the 20 patients showed improvement in terms of oxygen intake, lung lesion opacity (in 19 patients), lymphocytes in peripheral blood (10 patients), C-reactive protein (16 patients) and further, all patients were discharged on average 15.1 d after giving tocilizumab in a study conducted in China between 5 and 14 February 2020 [ 169 ]. A study on 100 COVID-19 patients with severe pneumonia treated with tocilizumab and other supportive therapy from 9–20 March 2020 in Italy, the respiratory condition was improved or stabilized in 77 patients in 10 days. 61 of these 77 patients had shown clearing of diffuse bilateral opacities on chest X-ray and 15 were discharged from the hospital; however, respiratory condition of 23 patients was worse during the treatment and 20 died out of 23 patients [ 170 ]. In another clinical study, tocilizumab administration showed a reduction in serum IL-6 level in 10 patients out of 15 patients, however, it could not decrease IL-6 level in four patients. Still, observations suggest that tocilizumab is a good treatment option in patients who have a risk of cytokine storms [ 171 ]. However, it is difficult to reach on a conclusion regarding the use of tocilizumab in COVID-19 patients with the limited number of clinical sample size.

The absolute bioavailability of tocilizumab following subcutaneous administration was estimated to be 79.5% [ 172 ]. Tocilizumab is eliminated from the body in a concentration-dependent manner. Therefore, its half-life is directly proportional to its serum concentration. At higher serum concentration, it shows linear elimination and has the terminal half-life of 21.5 days ( https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/125276s127,125472s040lbl.pdf ).

The notable adverse effect of tocilizumab is liver toxicity. Steatosis, steatohepatitis and focal hepatocellular necrosis were seen in this drug-induced hepatotoxicity. Other common adverse reactions observed were skin and soft tissue infections, dyslipidemia, transient neutropenia, headache, nausea and flu-like symptoms. Therefore, a full assessment for liver injury and dose adjustment is required in patients administered with tocilizumab [ 173 , 174 ]. Tocilizumab also showed good efficacy in long term dosing for rheumatoid arthritis with similar adverse reactions and few malignancies also were reported [ 175 ].

Other probable potential re-tasking agents for the treatment of COVID-19

In a recent study, it has been demonstrated that an antiprotozoal agent nitazoxanide has shown antiviral activity against a number of viruses which include human and animal coronaviruses. It is used orally and chemically, this drug is nitrothiazoly-salicylamide, a broad-spectrum anthelmintic and antiviral prodrug which is metabolized to an active compound tizoxanide [ 176 , 177 ] (Table 2 ). It had shown inhibitory potential against SARS-CoV2 at a low-concentration with 50% effective concentration of 2.12 μM in Vero E6 cells. It has been observed that antiviral activity of this compound may be due to interference with host-regulated pathways which are involved in viral replication rather than virus-specific pathways [ 178 , 179 ].

Nafamostat is an anticoagulant in nature and further, its activity was also evaluated in the Vero E6 cells infected with SARS-CoV2. This drug is a synthetic serine protease inhibitor and inhibited the SARS-CoV2 at 50% effective concentration of 22.50 μM in Vero E6 cells. Further, it is speculated that it may act through the inhibition of membrane fusion by reducing the release of cathepsin B. As this agent has previously shown potential against the MERS-CoV through prevention of membrane fusion, it could also be recommended for further in-vivo evaluation against COVID-19 [ 29 ] (Fig. 2 ; Table 2 ). Fig. 2 Overview of the drugs with potential for repurposing against COVID-19. The drugs being considered for primary therapy of COVID either acts on targets of the virus or on the targets of the host

Ivermectin is a broad-spectrum anti-parasitic agent and has also shown efficacy against some viral infections. This drug is basically a macrolide endectocide macrocyclic lactone derived from Streptomyces avermitilis with anthelmintic activity (Table 2 ). Recently, this drug has been investigated against SARS-CoV2 in in-vitro cell culture system in Australia. It reduced the viral RNA of SARS-CoV2 at two hours post infection in Vero-hSLAM cells with the addition of single dose and its reduction intensity was approximately 5000-fold. This study hypothesized that ivermectin may act through inhibition of importin (IMP) α/β1-mediated nuclear import of viral proteins similar to other RNA viruses, however; further investigation is required to understand the precise mechanism of action in SARS-CoV2 [ 180 ]. It is also important to conduct the trials in in-vivo animal models and further, the pre-clinical trials in human beings are also required with fast pace if in-vivo models results have potential to mitigate the COVID-19 infection (Fig. 2 ).

Cepharanthine, a naturally occurring plant alkaloid, is an anti-inflammatory and anti-neoplastic and is approved for leukopenia treatment (Table 2 ). Cepharanthine showed the most potent inhibition of GX_P2V infection and decreased the viral RNA yield in the pangolin coronavirus GX_P2V workable model, therefore, this therapeutic agent may also be a potential candidate for repurposing against COVID-19 [ 181 ]. Further, it has been speculated that this drug may target host cell pathways [ 181 ].

A gold-containing triethyl phosphine coated drug, auranofin, is used as therapy for the arthritis and approved from FDA for this treatment (Table 2 ). Previously, this drug has shown effects against viral, bacterial and parasitic infections. Recently, auranofin has shown inhibitory effect against viral RNA in Huh7 cells infected with SARS-CoV2 as well as a reduction in proinflammatory cytokines in an in-vitro study [ 182 ]. Endoplasmic reticulum (ER) stress and unfolded protein response (UPR) activation are responsible for the viral replication and pathogenesis in coronavirus infection [ 182 , 183 ] and high levels of UPR activation has been recorded in the cells which have higher expression of SARS-COV spike protein [ 182 , 184 , 185 ]. Therefore, it is speculated that auranofin may act through the inhibition of redox enzymes such as thioredoxin reductase and induction of ER stress, however, its confirmatory investigation is required [ 182 , 186 ].

Janus Kinase inhibitors have anti-inflammatory and antiviral effects and may have a purported advantage over other immunomodulatory strategies in COVID-19 [ 187 ]. JAK1/2 inhibitor ruxolitinib, baricitinib, JAK 1/3 inhibitor tofacitinib and pan-JAK inhibitor TD-0903 are presently under different phases of clinical trial and being investigated for COVID-19 treatment ( https://www.pharmaceutical-technology.com/comment/incyte-eli-lilly-jak-inhibitor-covid-19/ ). A phase-I clinical study showed improvement in COVID-19 inflammation score with clinical improvement by ruxolitinib. However, it has toxicity on the liver and hematopoietic system. But in this study with the short term dosage, it did not show any major adverse events [ 188 ]. Baricitinib is presently under phase-III clinical trial ( https://www.clinicaltrialsarena.com/news/lilly-baricitinib-covid-19-trial/ ). Initial studies showed the drug baricitinib corrected the immune dysregulation and improved clinical disease outcome with no serious adverse events [ 189 , 190 ]. All the above drugs are under different phases of clinical trials and none have been approved for the treatment of COVID-19.

Dexamethasone is a corticosteroid and it has been used in some clinical trials. The preliminary results of RECOVERY trial conducted in 2104 patients showed dexamethasone @ 6 mg once daily for up to 10 days showed improvement in recovery with 22.9% mortality in the dexamethasone group compared to the 25.7% mortality in the usual care group [ 191 ]. However, few concerns have been raised on RECOVERY trial outcome in choosing the correct steroid and dose. In another study, methylprednisolone reduced the mortality rates in COVID-19 patients with ARDS. Further, the effect of dexamethasone in geriatric patients and effects on viral load are not mentioned in the RECOVERY trial [ 192 ]. Theoharides and Conti have also suggested restricting the use of dexamethasone during the initial phase of disease in severely ill patients for shorter period. Using this drug in recovery phase may lead to reduced viral clearance and nosocomial infections [ 193 ]. As it suppresses immunity and it may aggravate some latent infections whose occurrence is of no importance to the developed countries. Therefore, region-specific study is required before incorporating into COVID-19 therapy [ 194 ].

Molecular docking and computational modelling based approach to identify the therapeutic candidates for repurposing against COVID-19

A chemotherapeutic fluoroquinolone antibiotic, prulifloxacin, with broad-spectrum activity, and some anti-HIV drugs such as tegobuvir, (a novel non-nucleoside inhibitor of human coronavirus RNA replication), nelfinavir (a protease inhibitor which inhibits the cleavage of the polyprotein gag-pol) and bictegravir (HIV-1 integrase inhibitor) have protein binding sites of the proteases which have been shown using the high throughput screening as molecular docking with bioinformatics analysis and would be considered the potential candidates for re-tasking against COVID-19 in future [ 195 ] and in-vitro and in-vivo animal models may provide a lead against this disease. According to another recent molecular docking study based on RDRP modelling and multiple sequence alignment (MSA) showed a binding capacity to RDRP against SARS-CoV2 by various antiviral agents such as sofosbuvir (FDA approved against Hepatitis C virus), ribavirin, remdesivir and IDX-184; (under clinical trial against Hepatitis C virus) [ 196 ]. Elbasvir, an antiviral drug, (approved for the treatment of hepatitis C) has shown predicted multiple binding sites at RDRP, papain-like proteinase and helicase of SARS-CoV2 using the docking simulations and computational modelling [ 197 ] (Fig. 2 ; Table 2 ).

In a recent review, it has been stated that azithromycin, quercetin, rapamycin and doxycycline may have senolytic activity and azithromycin and doxycycline are used to inhibit viral replication and IL-6 production, therefore, these therapeutic agents may be potential re-tasking agents against COVID-19 in future with proof of sufficient in-vitro and in-vivo studies [ 198 ] (Fig. 2 ; Table 2 ).

Peptide (EK1), TDF, 3TC (RNA synthesis inhibitors), ShuFeng JieDu and Lianhuaqingwen capsules (Chinese traditional medicine) are screened using standard bioassays, chemical screening and genome and biophysical understanding of the targeted virus for being the potential drug candidates against SARS-CoV2 infection as described in a recent review. However, the efficacy and safety of these drugs for SARS-CoV2 still need to be further confirmed by clinical experiments [ 93 ] (Fig. 2 ).

Future perspective and conclusion

COVID-19 is a pandemic and has no treatment till date including vaccine and drugs. However, there are number of available drugs with approval of FDA for treatment of other diseases which could be used on the basis of the trial against COVID-19 and considered as the repurposed drugs. These are antivirals, antimalarials, ACEIs, ARBs, statins and monoclonal antibodies. It has been noticed that remdesivir, favipiravir, ribavirin, lopinavir-ritonavir combination, arbidol, tocilizumab have shown benefits in various clinical studies done on the basis of compassionate use to save the life of COVID-19 patients; therefore, in future, these drugs could be the potential drug therapy against this deadly disease. However, the use of chloroquine and hydroxychloroquine has shown the controversial results in the different trials, therefore, WHO also stopped their SOLIDARITY trials recently. In future, chloroquine and hydroxychloroquine require a large number of research studies to reach a conclusion for its use in COVID-19 patients. Further, ACEIs and ARBs could be the potential supportive therapy against this infection. Some drugs are in the early phase of investigation like ivermectin and auranofin to be used against the COVID-19 and these agents could be potential therapeutic agents in future. Molecular docking would be the central technique to identify the probable therapeutic agents against COVID-19 patients and the screened agents, thereby, could be verified for their effectiveness in in-vitro and in-vivo studies.

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References

1. Huang F Zhang C Liu Q Zhao Y Zhang Y Qin Y Identification of amitriptyline HCl, flavin adenine dinucleotide, azacitidine and calcitriol as repurposing drugs for influenza A H5N1 virus-induced lung injury PLoS Pathog. 2020 16 3 e1008341 10.1371/journal.ppat.1008341 32176725 PMC7075543

2. Scherman D Fetro C Drug repositioning for rare diseases: Knowledge-based success stories Therapie. 2020 75 161 167 10.1016/j.therap.2020.02.007 32164975

3. Dyall J Coleman CM Hart BJ Venkataraman T Holbrook MR Kindrachuk J Repurposing of clinically developed drugs for treatment of Middle East respiratory syndrome coronavirus infection Antimicrob Agents Chemother. 2014 58 4885 4893 10.1128/AAC.03036-14 24841273 PMC4136000

4. Sertkaya A, Birkenbach A, Berlind A, Eyraud J. Examination of clinical trial costs and barriers for drug development. US Department of Health and Human Services, office of the assistant secretary for planning and evaluation report. 2014;1:1–92.

5. Yeu Y Yoon Y Park S Protein localization vector propagation: a method for improving the accuracy of drug repositioning Mol Biosyst. 2015 11 2096 2102 10.1039/c5mb00306g 25998487

6. Hodos RA Kidd BA Shameer K Readhead BP Dudley JT In silico methods for drug repurposing and pharmacology Wiley Interdiscip Rev Syst Biol Med. 2016 8 186 210 10.1002/wsbm.1337 27080087 PMC4845762

7. Pushpakom S Iorio F Eyers PA Escott KJ Hopper S Wells A Drug repurposing: progress, challenges and recommendations Nat Rev Drug Discov. 2019 18 1 41 58 10.1038/nrd.2018.168 30310233

8. Paolini GV Shapland RH van Hoorn WP Mason JS Hopkins AL Global mapping of pharmacological space Nat Biotechnol. 2006 24 805 815 10.1038/nbt1228 16841068

9. Koch U Hamacher M Nussbaumer P Cheminformatics at the interface of medicinal chemistry and proteomics Biochim Biophys Acta. 2014 1844 156 161 10.1016/j.bbapap.2013.05.010 23707564

10. Piro RM Network medicine: linking disorders Hum Genet. 2012 131 1811 1820 10.1007/s00439-012-1206-y 22825316

11. Zhou Y Hou Y Shen J Huang Y Martin W Cheng F Network-based drug repurposing for novel coronavirus 2019-nCoV/SARS-CoV-2 Cell Discov. 2020 6 14 10.1038/s41421-020-0153-3 32194980 PMC7073332

12. Li X, Yu J, Zhang Z, Ren J, Peluffo AE, Zhang W, et al.Network bioinformatics analysis provides insight into drug repurposing for COVID-2019. Preprints 2020, 2020030286 (doi: 10.20944/preprints202003.0286.v1. 10.1016/j.medidd.2021.100090 PMC8008783 33817623

13. Tai W He L Zhang X Pu J Voronin D Jiang S Characterization of the receptor-binding domain (RBD) of 2019 novel coronavirus: implication for development of RBD protein as a viral attachment inhibitor and vaccine Cell Mol Immunol. 2020 17 613 620 10.1038/s41423-020-0400-4 32203189 PMC7091888

14. Wang N Shi X Jiang L Zhang S Wang D Tong P Structure of MERS-CoV spike receptor-binding domain complexed with human receptor DPP4 Cell Res. 2013 23 8 986 993 10.1038/cr.2013.92 23835475 PMC3731569

15. Du L He Y Zhou Y Liu S Zheng BJ Jiang S The spike protein of SARS-CoV-a target for vaccine and therapeutic development Nat Rev Microbiol. 2009 7 226 236 10.1038/nrmicro2090 19198616 PMC2750777

16. Zumla A Chan JF Azhar EI Hui DS Yuen KY Coronaviruses-drug discovery and therapeutic options Nat Rev Drug Discov. 2016 15 327 347 10.1038/nrd.2015.37 26868298 PMC7097181

17. Harrison C Coronavirus puts drug repurposing on the fast track Nat Biotechnol. 2020 38 4 379 381 10.1038/d41587-020-00003-1 32205870

18. Woodhead M Ewig S Torres A Severe acute respiratory syndrome (SARS) Eur Respir J. 2003 21 739 740 10.1183/09031936.03.00035403 12765412

19. Zaki AM Boheemena S Bestebroer TIM Osterhaus A Fouchier R Isolation of a novel coronavirus from a man with pneumonia in Saudi Arabia N Engl J Med. 2012 367 1814 1820 10.1056/NEJMoa1211721 23075143

20. Woo PC Huang Y Lau SK Yuen KY Coronavirus genomics and bioinformatics analysis Viruses 2010 2 1804 1820 10.3390/v2081803 21994708 PMC3185738

21. Drexler JF Gloza-Rausch F Glende J Corman VM Muth D Goettsche M Genomic characterization of severe acute respiratory syndrome-related coronavirus in European bats and classification of coronaviruses based on partial RNA-dependent RNA polymerase gene sequences J Virol 2010 2010 84 11336 11349 10.1128/JVI.00650-10 PMC2953168 20686038

22. LeDuc JW Barry MA SARS, the first pandemic of the 21st century Emerg Infect Dis 2004 10 e26 10.3201/eid1011.040797_02

23. Zhou P Yang XL Wang XG Hu B Zhang L Zhang W A pneumonia outbreak associated with a new coronavirus of probable bat origin Nature 2020 579 270 273 10.1038/s41586-020-2012-7 32015507 PMC7095418

24. Benvenuto D Giovanetti M Ciccozzi A Spoto S Angeletti S Ciccozzi M The 2019-new coronavirus epidemic: evidence for virus evolution J Med Virol. 2020 92 455 459 10.1002/jmv.25688 31994738 PMC7166400

25. Shield C. Coronavirus: From bats to pangolins, how do viruses reach us?. Deutsche Welle. 7 February 2020. Retrieved 13 March 2020.

26. Gorbalenya AE Baker SC Baric RS de Groot RJ Drosten C Gulyaeva AA The species severe acute respiratory syndrome-related coronavirus: classifying 2019-nCoV and naming it SARS-CoV-2 Nat Microbiol. 2020 5 536 544 10.1038/s41564-020-0695-z 32123347 PMC7095448

27. Baron SA, Devaux C, Colson P, Raoult D, Rolain JM. Teicoplanin: an alternative drug for the treatment of coronavirus COVID-19? Int J Antimicrob Agents. 2020:105944. doi: 10.1016/j.ijantimicag.2020.105944. 10.1016/j.ijantimicag.2020.105944 PMC7102624 32179150

28. Ahmed SF Quadeer AA McKay MR Preliminary identification of potential vaccine targets for the COVID-19 Coronavirus (SARS-CoV-2) based on SARS-CoV immunological studies Viruses 2020 12 3 E254 10.3390/v12030254 32106567 PMC7150947

29. Wang M Cao R Zhang L Yang X Liu J Xu M Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro Cell Res 2020 30 269 271 10.1038/s41422-020-0282-0 32020029 PMC7054408

30. de Wit E Feldmann F Cronin J Jordan R Okumura A Thomas T Prophylactic and therapeutic remdesivir (GS-5734) treatment in the rhesus macaque model of MERS-CoV infection Proc Natl Acad Sci USA 2020 117 12 6771 6776 10.1073/pnas.1922083117 32054787 PMC7104368

31. Sheahan TP Sims AC Graham RL Menachery VD Gralinski LE Case JB Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses Sci Transl Med. 2017 9 eaal3653 10.1126/scitranslmed.aal3653 28659436 PMC5567817

32. Holshue ML DeBolt C Lindquist S Lofy KH Wiesman J Bruce H First case of 2019 novel coronavirus in the United States N Engl J Med 2020 382 929 936 10.1056/NEJMoa2001191 32004427 PMC7092802

33. Nicastri E Petrosillo N Bartoli TA Lepore L Mondi A Palmieri F National Institute for the infectious diseases "L. Spallanzani", IRCCS. Recommendations for COVID-19 clinical management Infect Dis Rep 2020 12 8543 10.4081/idr.2020.8543 32218915 PMC7097833

34. Grein J Ohmagari N Shin D Diaz G Asperges E Castagna A Compassionate use of remdesivir for patients with severe Covid-19 N Engl J Med 2020 382 2327 2336 10.1056/NEJMoa2007016 32275812 PMC7169476

35. Beigel JH, Tomashek KM, Dodd LE, Mehta AK, Zingman BS, Kalil AC, et al. Remdesivir for the treatment of Covid-19-preliminary report. N Engl J Med. 2020;NEJMoa2007764. doi: 10.1056/NEJMoa2007764. 10.1056/NEJMc2022236 32649078

36. Wang Y Zhang D Du G Du R Zhao J Jin Y Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial Lancet 2020 395 1569 1578 10.1016/S0140-6736(20)31022-9.Erratum.In:Lancet.2020;395:1694.d 32423584 PMC7190303

37. Goldman JD Lye DCB Hui DS Marks KM Bruno R Montejano R Remdesivir for 5 or 10 days in patients with severe Covid-19 N Engl J Med 2020 10.1056/NEJMoa2015301 32459919 PMC7377062

38. Gordon CJ Tchesnokov EP Feng JY Porter DP Gotte M The antiviral compound remdesivir potently inhibits RNA-dependent RNA polymerase from Middle East respiratory syndrome coronavirus J Biol Chem 2020 295 15 4773 4779 10.1074/jbc.AC120.013056 32094225 PMC7152756

39. Agostini ML, Andres EL, Sims AC, Graham RL, Sheahan TP, Lu X, et al. Coronavirus susceptibility to the antiviral remdesivir (GS-5734) is mediated by the viral polymerase and the proofreading exoribonuclease. mBio. 2018;9(2):e00221–18. doi: 10.1128/mBio.00221–18. 10.1128/mBio.00221-18 PMC5844999 29511076

40. Warren TK Jordan R Lo MK Ray AS Mackman RL Soloveva V Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys Nature 2016 531 381 385 10.1038/nature17180 26934220 PMC5551389

41. Dong L Hu S Gao J Discovering drugs to treat coronavirus disease 2019 (COVID-19) Drug Discov Ther. 2020 14 58 60 10.5582/ddt.2020.01012 32147628

42. Oestereich L Lüdtke A Wurr S Rieger T Muñoz-Fontela C Günther S Successful treatment of advanced Ebola virus infection with T-705 (favipiravir) in a small animal model Antiviral Res. 2014 105 17 21 10.1016/j.antiviral.2014.02.014 24583123

43. Jordan PC Stevens SK Deval J Nucleosides for the treatment of respiratory RNA virus infections Antivir Chem Chemother. 2018 26 2040206618764483 10.1177/2040206618764483 29562753 PMC5890544

44. Pires de Mello CP, Tao X, Kim TH, Vicchiarelli M, Bulitta JB, Kaushik A, et al. Clinical regimens of favipiravir inhibit zika virus replication in the hollow-fiber infection model. Antimicrob Agents Chemother. 2018;62:e00967–18. doi: 10.1128/AAC.00967-18. 10.1128/AAC.00967-18 PMC6125552 29967017

45. Nguyen TH Guedj J Anglaret X Laouénan C Madelain V Taburet AM Favipiravir pharmacokinetics in Ebola-Infected patients of the JIKI trial reveals concentrations lower than targeted PLoS Negl Trop Dis. 2017 11 e0005389 10.1371/journal.pntd.0005389 28231247 PMC5340401

46. Du YX Chen XP Favipiravir: pharmacokinetics and concerns about clinical trials for 2019-nCoV infection Clin Pharmacol Ther. 2020 10.1002/cpt.1844 32246834

47. Gowen BB Sefing EJ Westover JB Smee DF Hagloch J Furuta Y Alterations in favipiravir (T-705) pharmacokinetics and biodistribution in a hamster model of viral hemorrhagic fever Antiviral Res. 2015 121 132 137 10.1016/j.antiviral.2015.07.003 26186980 PMC4536130

48. Mendenhall M Russell A Smee DF Hall JO Skirpstunas R Furuta Y Effective oral favipiravir (t-705) therapy initiated after the onset of clinical disease in a model of arenavirus hemorrhagic fever PLoS Negl Trop Dis. 2011 5 e1342 10.1371/journal.pntd.0001342 22022624 PMC3191123

49. Reagan-Shaw S Nihal M Ahmad N Dose translation from animal to human studies revisited FASEB J. 2008 22 659 661 10.1096/fj.07-9574LSF 17942826

50. Chu CM Cheng VC Hung IF Wong MM Chan KH Chan KS Role of lopinavir/ritonavir in the treatment of SARS: initial virological and clinical findings Thorax 2004 59 3 252 256 10.1136/thorax.2003.012658 14985565 PMC1746980

51. Falzarano D De Wit E Rasmussen AL Feldmann F Okumura A Scott DP Treatment with interferon-α2b and ribavirin improves outcome in MERS-CoV–infected rhesus macaques Nat Med. 2013 19 1313 1317 10.1038/nm.3362 24013700 PMC4093902

52. Graci JD Cameron CE Mechanisms of action of ribavirin against distinct viruses Rev Med Virol. 2006 16 37 48 10.1002/rmv.483 16287208 PMC7169142

53. Preston SL Drusano GL Glue P Nash J Gupta SK McNamara P Pharmacokinetics and absolute bioavailability of ribavirin in healthy volunteers as determined by stable-isotope methodology Antimicrob Agents Chemother. 1999 43 2451 2456 10.1128/AAC.43.10.2451 10508023 PMC89499

54. Loustaud-Ratti V Stanke-Labesque F Marquet P Gagnieu MC Maynard M Babany G Optimizing ribavirin dosage: a new challenge to improve treatment efficacy in genotype 1 hepatitis C patients Gastroenterol Clin Biol. 2009 33 580 583 10.1016/j.gcb.2009.04.009 19481390

55. Molina-Cuadrado E Mateo-Carrrasco H Collado A Casado MM Anaemia predictors in patients with chronic hepatitis C treated with ribavirin and direct-acting antiviral agents Eur J Hosp Pharm. 2018 25 132 137 10.1136/ejhpharm-2017-001277 31157007 PMC6452397

56. Russmann S Grattagliano I Portincasa P Palmieri VO Palasciano G Ribavirin-induced anemia: mechanisms, risk factors and related targets for future research Curr Med Chem. 2006 13 3351 3357 10.2174/092986706778773059 17168855

57. Naik GS Tyagi MG A pharmacological profile of ribavirin and monitoring of its plasma concentration in chronic hepatitis C infection J Clin Exp Hepatol. 2012 2 42 54 10.1016/S0973-6883(12)60090-5 25755405 PMC3940409

58. Morello J Rodríguez-Novoa S Jiménez-Nácher I Soriano V Usefulness of monitoring ribavirin plasma concentrations to improve treatment response in patients with chronic hepatitis C J Antimicrob Chemother. 2008 62 1174 1180 10.1093/jac/dkn421 18931138

59. Chen YK, Huang YQ, Tang SQ, Xu XL, Zeng YM, He XQ et al. Comparative effectiveness and safety of ribavirin plus interferon-alpha, lopinavir/ritonavir plus interferon-alpha and ribavirin plus lopinavir/ritonavir plus interferon-alpha in patients with mild to moderate novel coronavirus pneumonia: results of a randomized, open-labeled prospective study (4/14/2020). SSRN: https://ssrn.com/abstract=3576905 or 10.2139/ssrn.3576905.

60. Wu C Liu Y Yang Y Zhang P Zhong W Wang Y Analysis of therapeutic targets for SARS-CoV-2 and discovery of potential drugs by computational methods. Version 2 Acta Pharm Sin B. 2020 10 766 788 10.1016/j.apsb.2020.02.008 32292689 PMC7102550

61. Chen YW, Yiu CB, Wong KY. Prediction of the SARS-CoV-2 (2019-nCoV) 3C-like protease (3CL pro) structure: virtual screening reveals velpatasvir, ledipasvir, and other drug repurposing candidates. F1000Res. 2020;9:129. doi: 10.12688/f1000research.22457.2. 10.12688/f1000research.22457.1 PMC7062204 32194944

62. Savarino A Expanding the frontiers of existing antiviral drugs: possible effects of HIV-1 protease inhibitors against SARS and avian influenza J Clin Virol 2005 34 170 178 10.1016/j.jcv.2005.03.005 15893956 PMC7108403

63. Ngo ST Quynh Anh Pham N Le Thi L Pham DH Vu VV Computational determination of potential inhibitors of SARS-CoV-2 main protease J Chem Inf Model 2020 10.1021/acs.jcim.0c00491 32530282

64. Martinez MA Compounds with therapeutic potential against novel respiratory 2019 coronavirus Antimicrob Agents Chemother. 2020 64 e00399 e420 10.1128/AAC.00399-20 32152082 PMC7179632

65. Chandwani A Shuter J Lopinavir/ritonavir in the treatment of HIV-1 infection: a review Ther Clin Risk Manag. 2008 4 1023 1033 10.2147/tcrm.s3285 19209283 PMC2621403

66. Ortega JT Serrano ML Pujol FH Rangel HR Unrevealing sequence and structural features of novel coronavirus using in silico approaches: the main protease as molecular target EXCLI J. 2020 19 400 409 10.17179/excli2020-1189 32210741 PMC7081067

67. Lim J, Jeon S, Shin HY, Kim MJ, Seong YM, LeeWJ, et al. Case of the index patient who caused tertiary transmission of COVID-19 infection in Korea: the application of lopinavir/ritonavir for the treatmentof COVID-19 infected pneumonia monitored by quantitative RT-PCR. J Korean Med Sci. 2020;35:e79. doi: 10.3346/jkms.2020.35.e79. 10.3346/jkms.2020.35.e79 PMC7025910 32056407

68. Xu K, Cai H, Shen Y, Ni Q, Chen Y, Hu S, et al. Management of corona virus disease-19 (COVID-19): the Zhejiang experience. Zhejiang Da Xue Xue Bao Yi Xue Ban. 2020 21;49:0. 10.3785/j.issn.1008-9292.2020.02.02 PMC8800711 32391658

69. Han W Quan B Guo Y Zhang J Lu Y Feng G The course of clinical diagnosis and treatment of a case infected with coronavirus disease 2019 J Med Virol 2020 92 461 463 10.1002/jmv.25711 32073161 PMC7167012

70. Qiu H Wu J Hong L Luo Y Song Q Chen D Clinical and epidemiological features of 36 children with coronavirus disease 2019 (COVID-19) in Zhejiang, China: an observational cohort study Lancet Infect Dis 2020 20 689 696 10.1016/S1473-3099(20)30198-5 32220650 PMC7158906

71. Ton AT Gentile F Hsing M Ban F Cherkasov A Rapid identification of potential inhibitors of SARS-CoV-2 main protease by deep docking of 1.3 billion compounds Mol Inform 2020 10.1002/minf.202000028 32162456 PMC7228259

72. Cao B Wang Y Wen D Liu W Wang J Fan G A trial of lopinavir-ritonavir in adults hospitalized with severe Covid-19 N Engl J Med. 2020 382 19 1787 1799 10.1056/NEJMoa2001282 32187464 PMC7121492

73. Wang Z Chen X Lu Y Chen F Zhang W Clinical characteristics and therapeutic procedure for four cases with 2019 novel coronavirus pneumonia receiving combined Chinese and Western medicine treatment Biosci Trends. 2020 14 64 68 10.5582/bst.2020.01030 32037389

74. Neuman MG Schneider M Nanau RM Parry C HIV-antiretroviral therapy induced liver, gastrointestinal, and pancreatic injury Int J Hepatol. 2012 2012 760706 10.1155/2012/760706 22506127 PMC3312274

75. Cvetkovic RS Goa KL Lopinavir/ritonavir: a review of its use in the management of HIV infection Drugs. 2003 63 769 802 10.2165/00003495-200363080-00004 12662125

76. Bongiovanni M Cicconi P Landonio S Meraviglia P Testa L Di Biagio A Predictive factors of lopinavir/ritonavir discontinuation for drug-related toxicity: results from a cohort of 416 multi-experienced HIV-infected individuals Int J Antimicrob Agents. 2005 26 88 91 10.1016/j.ijantimicag.2005.03.003 15878262

77. Robbins BL Capparelli EV Chadwick EG Yogev R Serchuck L Worrell C Pharmacokinetics of high-dose lopinavir-ritonavir with and without saquinavir or nonnucleoside reverse transcriptase inhibitors in human immunodeficiency virus-infected pediatric and adolescent patients previously treated with protease inhibitors Antimicrob Agents Chemother. 2008 52 3276 3283 10.1128/AAC.00224-08 18625762 PMC2533475

78. Canta F Marrone R Bonora S D'Avolio A Sciandra M Sinicco A Pharmacokinetics and hepatotoxicity of lopinavir/ritonavir in non-cirrhotic HIV and hepatitis C virus (HCV) co-infected patients J Antimicrob Chemother. 2005 55 280 281 10.1093/jac/dkh516 15650005

79. Sulkowski MS Thomas DL Chaisson RE Moore RD Hepatotoxicity associated with antiretroviral therapy in adults infected with human immunodeficiency virus and the role of hepatitis C or B virus infection JAMA 2000 283 74 80 10.1001/jama.283.1.74 10632283

80. Tu Y Poblete RJ Freilich BD Zarbin MA Bhagat N Retinal toxicity with ritonavir Int J Ophthalmol. 2016 9 640 642 10.18240/ijo.2016.04.29 27162744 PMC4853367

81. Pasquau Liaño J Hidalgo TC Chemical characteristics, mechanism of action and antiviral activity of darunavir Enferm Infecc Microbiol Clin. 2008 26 3 9 10.1016/s0213-005x(08)76547-9 19195453

82. Khan SA, Zia K, Ashraf S, Uddin R, Ul-Haq Z. Identification of chymotrypsin-like protease inhibitors of SARS-CoV-2 via integrated computational approach. J Biomol Struct Dyn. 2020:1–10. doi: 10.1080/07391102.2020.1751298. 10.1080/07391102.2020.1751298 32238094

83. Rittweger M Arastéh K Clinical pharmacokinetics of darunavir Clin Pharmacokinet. 2007 46 739 756 10.2165/00003088-200746090-00002 17713972

84. Back D Sekar V Hoetelmans RM Darunavir: pharmacokinetics and drug interactions Antivir Ther. 2008 13 1 13 18389894

85. Triant VA Siedner MJ Darunavir and cardiovascular risk: evaluating the data to inform clinical care J Infect Dis. 2020 221 498 500 10.1093/infdis/jiz482 31828327 PMC6996858

86. Xie S Chen XX Qiao S Li R Sun Y Xia S Identification of the RNA pseudoknot within the 3' end of the porcine reproductive and respiratory syndrome virus genome as a pathogen-associated molecular pattern to activate antiviral signaling via RIG-I and toll-like receptor 3 J Virol. 2018 92 e00097 e118 10.1128/JVI.00097-18 29618647 PMC5974490

87. Li J Lehmann C Chen X Romerio F Lu W Total chemical synthesis of human interferon alpha-2b via native chemical ligation J Pept Sci. 2015 21 554 560 10.1002/psc.2760 25810135 PMC4480187

88. Thomas H Foster G Platis D Mechanisms of action of interferon and nucleoside analogues J Hepatol. 2003 39 S93 S98 10.1016/s0168-8278(03)00207-1 14708685

89. Wang HQ Ma LL Jiang JD Pang R Chen YJ Li YH Recombinant human interferon alpha 2b broad-spectrum anti-respiratory viruses pharmacodynamics study in vitro Yao Xue Xue Bao. 2014 49 11 1547 1553 25757280

90. Yu DX Chen Q Zhang LL Liu Y Yu ZA Li ZF A field trial of recombinant human interferon alpha-2b for nasal spray to prevent SARS and other respiratory viral infections Zhonghua Shi Yan He Lin Chuang Bing Du Xue Za Zhi. 2005 19 216 219 16261200

91. Falzarano D De Wit E Martellaro C Callison J Munster VJ Feldmann H Inhibition of novel β coronavirus replication by a combination of interferon-α2b and ribavirin Sci Rep. 2013 3 1686 10.1038/srep01686 23594967 PMC3629412

92. Arabi YM Shalhoub S Mandourah Y Al-Hameed F Al-Omari A Al Qasim E Ribavirin and interferon therapy for critically ill patients with middle east respiratory syndrome: a multicenter observational study Clin Infect Dis. 2020 70 9 1837 1844 10.1093/cid/ciz544 31925415 PMC7108209

93. Lu H Drug treatment options for the 2019-new coronavirus (2019-nCoV) Biosci Trends. 2020 14 69 71 10.5582/bst.2020.01020 31996494

94. Shen KL Yang YH Diagnosis and treatment of, novel coronavirus infection in children: a pressing issue World J Pediatr. 2019 2020 1 3 10.1007/s12519-020-00344-6 PMC7091265 32026147

95. Foster GR Review article: pegylated interferons: chemical and clinical differences Aliment Pharmacol Ther. 2004 20 8 825 830 10.1111/j.1365-2036.2004.02170.x.96 15479353

96. Russo MW Fried MW Side effects of therapy for chronic hepatitis C Gastroenterology 2003 124 6 1711 1719 10.1016/s0016-5085(03)00394-9 12761728

97. Zheng L Li MP Gou ZP Wang Y Xu N Cai YM A pharmacokinetic and pharmacodynamic comparison of a novel pegylated recombinant consensus interferon-α variant with peginterferon-α-2a in healthy subjects Br J Clin Pharmacol. 2015 79 4 650 659 10.1111/bcp.12528 25297637 PMC4386949

98. Mainali NR Bhatt VR Kedia S Krishnamurthy J Wake LM Akhtari M Reversible bone marrow aplasia induced by pegylated interferon-α-2a therapy in a patient with primary myelofibrosis J Oncol Pharm Pract. 2014 20 5 386 392 10.1177/1078155213504444 24067929

99. Raison CL Demetrashvili M Capuron L Miller AH Neuropsychiatric adverse effects of interferon-alpha: recognition and management CNS Drugs 2005 19 105 123 10.2165/00023210-200519020-00002 15697325 PMC1255968

100. Arabi YM Alothman A Balkhy HH Al-Dawood A AlJohani S Al Harbi S Treatment of Middle East Respiratory Syndrome with a combination of lopinavir-ritonavir and interferon-β1b (MIRACLE trial): study protocol for a randomized controlled trial Trials. 2018 19 81 10.1186/s13063-017-2427-0 29382391 PMC5791210

101. Chan JF Yao Y Yeung ML Deng W Bao L Jia L Treatment with lopinavir/ritonavir or interferon-β1b improves outcome of MERS-CoV infection in a nonhuman primate model of common marmoset J Infect Dis. 2015 212 1904 1913 10.1093/infdis/jiv392 26198719 PMC7107395

102. Hung IF Lung KC Tso EY Liu R Chung TW Chu MY Triple combination of interferon beta-1b, lopinavir-ritonavir, and ribavirin in the treatment of patients admitted to hospital with COVID-19: an open-label, randomised, phase 2 trial Lancet 2020 395 1695 1704 10.1016/S0140-6736(20)31042-4 32401715 PMC7211500

103. Belouzard S Millet JK Licitra BN Whittaker GR Mechanisms of coronavirus cell entry mediated by the viral spike protein Viruses. 2012 4 1011 1033 10.3390/v4061011 22816037 PMC3397359

104. Hoffmann M Kleine-Weber H Schroeder S Krüger N Herrler T Erichsen S SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor Cell 2020 181 2 271 280.e8 10.1016/j.cell.2020.02.052 32142651 PMC7102627

105. Devaux CA Rolain JM Colson P Raoult D New insights on the antiviral effects of chloroquine against coronavirus: what to expect for COVID-19? Int J Antimicrob Agents. 2020 55 105938 10.1016/j.ijantimicag.2020.105938 32171740 PMC7118659

106. Al-Bari MAA Targeting endosomal acidification by chloroquine analogs as a promising strategy for the treatment of emerging viral diseases Pharmacol Res Perspect. 2017 5 1 e00293 10.1002/prp2.293 28596841 PMC5461643

107. Vincent MJ Bergeron E Benjannet S Erickson BR Rollin PE Ksiazek TG Chloroquine is a potent inhibitor of SARS coronavirus infection and spread Virol J. 2005 2 69 10.1186/1743-422X-2-69 16115318 PMC1232869

108. Liu J Cao R Xu M Wang X Zhang H Hu H Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro Cell Discov. 2020 6 16 10.1038/s41421-020-0156-0 32194981 PMC7078228

109. Mackenzie AH Dose refinements in long-term therapy of rheumatoid arthritis with antimalarials Am J Med. 1983 75 40 45 10.1016/0002-9343(83)91269-x 6869410

110. Laaksonen AL Koskiahde V Juva K Dosage of antimalarial drugs for children with juvenile rheumatoid arthritis and systemic lupus erythematosus. A clinical study with determination of serum concentrations of chloroquine and hydroxychloroquine Scand J Rheumatol. 1974 3 103 108 10.3109/03009747409115809 4608161

111. Weniger H, World Health Organization. Review of side effects and toxicity of chloroquine (No. WHO/MAL/79.906). 1979. Geneva: World health Organization.

112. McChesney EW Animal toxicity and pharmacokinetics of hydroxychloroquine sulfate Am J Med 1983 75 11 18 10.1016/0002-9343(83)91265-2 6408923

113. Popert AJ Chloroquine: a review Rheumatol Rehabil. 1976 15 235 238 10.1093/rheumatology/15.3.235 968356

114. Alving AS Eichelberger L Craige B Jones R Whorton CM Pullman TN Studies on the chronic toxicity of chloroquine J Clin Invest. 1948 27 60 65 10.1172/JCI101974 16695637 PMC438891

115. Looareesuwan S White NJ Chanthavanich P Edwards G Nicholl DD Bunch C Cardiovascular toxicity and distribution kinetics of intravenous chloroquine Br J Pharmacol. 1986 22 31 36 10.1111/j.1365-2125.1986.tb02876.x PMC1401074 3741724

116. Stokkermans TJ, Trichonas G. Chloroquine and hydroxychloroquine toxicity. [Updated 2019 Jun 4]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan-. https://www.ncbi.nlm.nih.gov/books/NBK537086/ . 30725771

117. Yusuf IH Sharma S Luqmani R Downes SM Hydroxychloroquine retinopathy Eye (Lond). 2017 31 828 845 10.1038/eye.2016.298 28282061 PMC5518824

118. Falcone PM Paolini L Lou PL Hydroxychloroquine toxicity despite normal dose therapy Ann Ophthalmol. 1993 25 385 388 8304691

119. Furst DE Pharmacokinetics of hydroxychloroquine and chloroquine during treatment of rheumatic diseases Lupus. 1996 5 11 15 10.1177/0961203396005001041 8803904

120. Ducharme J Farinotti R Clinical pharmacokinetics and metabolism of chloroquine. Focus on recent advancements Clin Pharmacokinet. 1996 31 4 257 274 10.2165/00003088-199631040-00003 8896943

121. Lim HS Im JS Cho JY Bae KS Klein TA Yeom JS Pharmacokinetics of hydroxychloroquine and its clinical implications in chemoprophylaxis against malaria caused by Plasmodium vivax Antimicrob Agents Chemother. 2009 53 1468 1475 10.1128/AAC.00339-08 19188392 PMC2663072

122. Browning DJ Pharmacology of Chloroquine and Hydroxychloroquine Hydroxychloroquine Chloroquine Retinopathy. 2014 4 35 63 10.1007/978-1-4939-0597-3_2

123. Melles RB Marmor MF Pericentral retinopathy and racial differences in hydroxychloroquine toxicity Ophthalmology 2015 122 110 116 10.1016/j.ophtha.2014.07.018 25182842

124. Wang X Cao R Zhang H Liu J Xu M Hu H The anti-influenza virus drug, arbidol is an efficient inhibitor of SARS-CoV-2 in vitro. Version 2 Cell Discov. 2020 6 28 10.1038/s41421-020-0169-8 32373347 PMC7195821

125. Leneva IA Fediakina IT Gus'kova TA Glushkov RG Sensitivity of various influenza virus strains to arbidol. Influence of arbidol combination with different antiviral drugs on reproduction of influenza virus A Ter Arkh. 2005 77 84 88 16206613

126. Shi L Xiong H He J Deng H Li Q Zhong Q Antiviral activity of arbidol against influenza A virus, respiratory syncytial virus, rhinovirus, coxsackie virus and adenovirus in vitro and in vivo Arch Virol. 2007 152 1447 1455 10.1007/s00705-007-0974-5 17497238

127. Blaising J Polyak SJ Pécheur EI Arbidol as a broad-spectrum antiviral: An update Antiviral Res. 2014 107 84 94 10.1016/j.antiviral.2014.04.006 24769245 PMC7113885

128. Khamitov RA Loginova S Shchukina VN Borisevich SV Maksimov VA Shuster AM Antiviral activity of arbidol and its derivatives against the pathogen of severe acute respiratory syndrome in the cell cultures Vopr Virusol. 2008 53 4 9 13 18756809

129. Barnard DL Kumaki Y Recent developments in anti-severe acute respiratory syndrome coronavirus chemotherapy Fut Virol. 2011 6 5 615 631 10.2217/fvl.11.33 PMC3136164 21765859

130. Wang Z Yang B Li Q Wen L Zhang R Clinical features of 69 cases with coronavirus disease, in Wuhan, China Clin Infect Dis. 2019 2020 272 10.1093/cid/ciaa272 PMC7184452 32176772

131. Rosa SGV Santos WC Clinical trials on drug repositioning for COVID-19 treatment Rev Panam Salud Publica. 2020 44 e40 10.26633/RPSP.2020.40 32256547 PMC7105280

132. Deng L Li C Zeng Q Liu X Li X Zhang H Arbidol combined with LPV/r versus LPV/r alone against Corona Virus Disease 2019: a retrospective cohort study J Infect 2020 81 e1 e5 10.1016/j.jinf.2020.03.002 32171872 PMC7156152

133. Titova ON Petrova MA Shklyarevich NA Kuzubova NA Aleksandrov AL Kovaleva LF Efficacy of Arbidol in the prevention of virus-induced exacerbations of bronchial asthma and chronic obstructive pulmonary disease Ter Arkh 2018 90 8 48 52 10.26442/terarkh201890848-52 30701939

134. Li Y, Xie Z, Lin W, Cai W, Wen C, Guan Y, et al. An exploratory randomized, controlled study on the efficacy and safety of lopinavir/ritonavir or arbidol treating adult patients hospitalized with mild/moderate COVID-19 (ELACOI). MedRxiv. https://www.medrxiv.org . doi: https://doi.org/10.1101/2020.03.19.20038984.

135. Deng P Zhong D Yu K Zhang Y Wang T Chen X Pharmacokinetics, metabolism, and excretion of the antiviral drug arbidol in humans Antimicrob Agents Chemother. 2013 57 1743 1755 10.1128/AAC.02282-12 23357765 PMC3623363

136. Fedson DS, Opal SM, Rordam OM. Hiding in plain sight: an approach to treating patients with severe COVID-19 infection. mBio. 2020;11:e00398-20. https://doi.org/10.1128/mBio.00398–20. 10.1128/mBio.00398-20 PMC7157814 32198163

137. Wösten-van Asperen RM Bos AP Bem RA Dierdorp BS Dekker T van Goor H Imbalance between pulmonary angiotensin- converting enzyme and angiotensin-converting enzyme 2 activity in acute respiratory distress syndrome Pediatr Crit Care Med. 2013 2013 14 e438 e441 10.1097/PCC.0b013e3182a55735 24226567

138. Vaduganathan M Vardeny O Michel T McMurray JJV Pfeffer MA Solomon SD Renin-angiotensin-aldosterone system inhibitors in patients with Covid-19 N Engl J Med. 2020 382 1653 1659 10.1056/NEJMsr2005760 32227760 PMC7121452

139. Wan Y Shang J Graham R Baric RS Li F Receptor recognition by novel coronavirus fromWuhan: An analysis based on decade-long structural studies of SARS J Virol. 2020 94 e00127 e220 10.1128/JVI.00127-20 31996437 PMC7081895

140. Steinberg BE Goldenberg NM Lee WL Do viral infections mimic bacterial sepsis? The role of microvascular permeability: a review of mechanisms and methods Antiviral Res. 2012 93 2 15 10.1016/j.antiviral.2011.10.019 22068147

141. Marin GH Facts and reflections on COVID-19 and anti-hypertensives drugs Drug Discov Ther. 2020 14 105 106 10.5582/ddt.2020.01017 32213760

142. Sun ML Yang JM Sun YP Su GH Inhibitors of RAS might be a good choice for the therapy of COVID-19 pneumonia Zhonghua Jie He He Hu Xi Za Zhi. 2020 43 219 222 10.3760/cma.j.issn.1001-0939.2020.03.016 32164092

143. Meng J Xiao G Zhang J He X Ou M Bi J Renin-angiotensin system inhibitors improve the clinical outcomes of COVID-19 patients with hypertension Emerg Microbes Infect. 2020 9 757 760 10.1080/22221751.2020.1746200 32228222 PMC7170368

144. Peng YD Meng K Guan HQ Leng L Zhu RR Wang BY Clinical characteristics and outcomes of 112 cardiovascular disease patients infected by 2019-nCoV Zhonghua Xin Xue Guan Bing Za Zhi. 2020 48 E004 10.3760/cma.j.cn112148-20200220-00105 32120458

145. D'Ardes D Boccatonda A Rossi I Guagnano MT Santilli F Cipollone F COVID-19 and RAS: unravelling an unclear relationship Int J Mol Sci. 2020 21 3003 10.3390/ijms21083003 PMC7215550 32344526

146. Peyriere H Eiden C Macia JC Reynes J Antihypertensive drugs in patients treated with antiretrovirals Ann Pharmacother. 2012 46 703 709 10.1345/aph.1Q546 22550277

147. Foy M Sperati CJ Lucas GM Estrella MM Drug interactions and antiretroviral drug monitoring Curr HIV/AIDS Rep. 2014 11 212 222 10.1007/s11904-014-0212-1 24950731 PMC4126905

148. Barreras A Gurk-Turner C Angiotensin II receptor blockers Proc (Bayl Univ Med Cent) 2003 16 123 126 10.1080/08998280.2003.11927893 16278727 PMC1200815

149. Israili ZH Clinical pharmacokinetics of angiotensin II (AT1) receptor blockers in hypertension J Hum Hypertens. 2000 14 S73 86 10.1038/sj.jhh.1000991 10854085

150. Domenic A Sica, Pharmacology and clinical efficacy of angiotensin receptor blockers Am J Hypertens. 2001 14 242 247 10.1016/S0895-7061(01)02134-3 11459213

151. Phadke M Saunik S COVID-19 treatment by repurposing drugs until the vaccine is in sight Drug Dev Res. 2020 10.1002/ddr.21666.10.1002/ddr.21666 32227357 PMC7228332

152. Tikoo K Patel G Kumar S Karpe PA Sanghavi M Malek V Tissue specific up regulation of ACE2 in rabbit model of atherosclerosis by atorvastatin: role of epigenetic histone modifications Biochem Pharmacol. 2015 93 343 351 10.1016/j.bcp.2014.11.013 25482567

153. Ferrario CM ACE 2: more of Ang 1–7 or less Ang II? Curr Opin Nephrol Hypertens. 2011 20 1 6 10.1097/MNH.0b013e3283406f57 21045683 PMC5826562

154. Fedson DS (2016) Treating the host response to emerging virus diseases:lessons learned from sepsis, pneumonia, influenza and Ebola. Ann Transl Med. 4:421. https://doi.org/10.21037/atm.2016.11.03. 10.21037/atm.2016.11.03 PMC5124618 27942512

155. Wösten-van Asperen RM Lutter R Specht PA Moll GN van Woensel JB van der Loos CM Acute respiratory distress syndrome leads to reduced ratio of ACE/ACE2 activities and is prevented by angiotensin-(1–7) or an angiotensin II receptor antagonist J Pathol 2011 225 618 627 10.1002/path.2987 22009550

156. Yuan S (2015) Statins may decrease the fatality rate of Middle East respiratory syndrome infection. mBio. 6:e01120-15. doi: 10.1128/mBio.01120-15. 10.1128/mBio.01120-15 PMC4542194 26265720

157. Totura AL, Baric RS. Reply to “statins may decrease the fatality rate of MERS infection”. mBio. 2015;6:e01303-15. doi: 10.1128/mBio.01303-15. 10.1128/mBio.01303-15 PMC4611038 26419878

158. Schachter M Chemical, pharmacokinetic and pharmacodynamic properties of statins: an update Fundam Clin Pharmacol 2005 19 117 125 10.1111/j.1472-8206.2004.00299.x 15660968

159. Bełtowski J Wójcicka G Jamroz-Wiśniewska A Adverse effects of statins-mechanisms and consequences Curr Drug Saf 2009 4 209 228 10.2174/157488609789006949 19534648

160. Mancini GB Baker S Bergeron J Fitchett D Frohlich J Genest J Diagnosis, prevention, and management of statin adverse effects and intolerance: canadian consensus working group update Can J Cardiol. 2016 32 S35 65 10.1016/j.cjca.2016.01.003 27342697

161. Burger D Back D Buggisch P Buti M Craxí A Foster G Clinical management of drug-drug interactions in HCV therapy: challenges and solutions J Hepatol. 2013 58 792 800 10.1016/j.jhep.2012.10.027 23137766

162. Chauvin B Drouot S Barrail-Tran A Taburet AM Drug-drug interactions between HMG-CoA reductase inhibitors (statins) and antiviral protease inhibitors Clin Pharmacokinet. 2013 52 815 831 10.1007/s40262-013-0075-4 23703578

163. Sheppard M Laskou F Stapleton PP Hadavi S Dasgupta B Tocilizumab (Actemra) Hum Vaccin Immunother. 2017 13 1972 1988 10.1080/21645515.2017.1316909 28841363 PMC5612212

164. Bersanelli M Controversies about COVID-19 and anticancer treatment with immune checkpoint inhibitors Immunotherapy. 2020 12 269 273 10.2217/imt-2020-0067 32212881 PMC7117596

165. Zhang X Song K Tong F Fei M Guo H Lu Z First case of COVID-19 in a patient with multiple myeloma successfully treated with tocilizumab Blood Adv. 2020 4 1307 1310 10.1182/bloodadvances.2020001907 32243501 PMC7160284

166. Ferrey AJ Choi G Hanna RM Chang Y Tantisattamo E Ivaturi K Case of novel coronavirus disease 19 in a chronic hemodialysis patient presenting with gastroenteritis and developing severe pulmonary disease Am J Nephrol. 2020 28 1 6 10.1159/000507417 PMC7179539 32222713

167. Mihai C Dobrota R Schröder M Garaiman A Jordan S Becker MO COVID-19 in a patient with systemic sclerosis treated with tocilizumab for SSc-ILD Ann Rheum Dis. 2020 79 668 669 10.1136/annrheumdis-2020-217442 32241792

168. Michot JM Albiges L Chaput N Saada V Pommeret F Griscelli F Tocilizumab, an anti-IL6 receptor antibody, to treat Covid-19-related respiratory failure: a case report Ann Oncol. 2020 31 961 964 10.1016/j.annonc.2020.03.300 32247642 PMC7136869

169. Xu X Han M Li T Sun W Wang D Fu B Effective treatment of severe COVID-19 patients with tocilizumab Proc Natl Acad Sci USA. 2020 117 10970 10975 10.1073/pnas.2005615117 32350134 PMC7245089

170. Toniati P Piva S Cattalini M Garrafa E Regola F Castelli F Tocilizumab for the treatment of severe COVID-19 pneumonia with hyperinflammatory syndrome and acute respiratory failure: a single center study of 100 patients in Brescia, Italy Autoimmun Rev. 2020 19 102568 10.1016/j.autrev.2020.102568 32376398 PMC7252115

171. Luo P Liu Y Qiu L Liu X Liu D Li J Tocilizumab treatment in COVID-19: a single center experience J Med Virol. 2020 92 814 818 10.1002/jmv.25801 32253759 PMC7262125

172. Abdallah H Hsu JC Lu P Fettner S Zhang X Douglass W Pharmacokinetic and pharmacodynamic analysis of subcutaneous tocilizumab in patients with rheumatoid arthritis from 2 randomized, controlled trials: SUMMACTA and BREVACTA J Clin Pharmacol. 2017 57 459 468 10.1002/jcph.826 27599663 PMC5363244

173. Jones G Ding C Tocilizumab: a review of its safety and efficacy in rheumatoid arthritis Clin Med Insights Arthritis Musculoskelet Disord. 2010 3 81 89 10.4137/CMAMD.S4864 21234291 PMC3018893

174. Mahamid M Mader R Safadi R Hepatotoxicity of tocilizumab and anakinra in rheumatoid arthritis: management decisions Clin Pharmacol. 2011 3 39 43 10.2147/CPAA.S24004 22287855 PMC3262392

175. Nishimoto N Miyasaka N Yamamoto K Kawai S Takeuchi T Azuma J Long-term safety and efficacy of tocilizumab, an anti-IL-6 receptor monoclonal antibody, in monotherapy, in patients with rheumatoid arthritis (the STREAM study): evidence of safety and efficacy in a 5-year extension study Ann Rheum Dis. 2009 68 1580 1584 10.1136/ard.2008.092866 19019888 PMC2732899

176. Rosenthal PJ (2017) Antiprotozoal drugs. In: Katzung BG (eds) Basic & clinical pharmacology, 14e. McGraw-Hill Education; New York.

177. Kelleni MT Nitazoxanide/azithromycin combination for COVID-19: a suggested new protocol for early management Pharmacol Res. 2020 157 104874 10.1016/j.phrs.2020.104874 32360581 PMC7192107

178. Rossignol JF Nitazoxanide, a new drug candidate for the treatment of Middle East respiratory syndrome coronavirus J Infect Public Health. 2016 9 227 230 10.1016/j.jiph.2016.04.001 27095301 PMC7102735

179. Şimşek Yavuz S Ünal S Antiviral treatment of COVID-19 Turk J Med Sci. 2020 50 611 619 10.3906/sag-2004-145 32293834 PMC7195979

180. Caly L Druce JD Catton MG Jans DA Wagstaff KM The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro Antiviral Res. 2020 3 104787 10.1016/j.antiviral.2020.104787 PMC7129059 32251768

181. Fan HH Wang LQ Liu WL An XP Liu ZD He XQ Repurposing of clinically approved drugs for treatment of coronavirus disease 2019 in a 2019-novel coronavirus (2019-nCoV) related coronavirus model Chin Med J (Engl). 2020 133 1051 1056 10.1097/CM9.0000000000000797 32149769 PMC7147283

182. Rothan HA Stone S Natekar J Kumari P Arora K Kumar M The FDA- approved gold drug auranofin inhibits novel coronavirus (SARSCOV-2) replication and attenuates inflammation in human cells Virology 2020 547 7 11 10.1016/j.virol.2020.05.002 32442105 PMC7236683

183. Fung TS Liu DX Coronavirus infection, ER stress, apoptosis and innate immunity Front Microbiol. 2014 5 296 10.3389/fmicb.2014.00296 24987391 PMC4060729

184. Siu KL Chan CP Kok KH Woo PC Jin DY Comparative analysis of the activation of unfolded protein response by spike proteins of severe acute respiratory syndrome coronavirus and human coronavirus HKU1 Cell Biosci. 2014 4 1 3 10.1186/2045-3701-4-3 24410900 PMC3930072

185. Sung SC Chao CY Jeng KS Yang JY Lai MM The 8ab protein of SARS-CoV is a luminal ER membrane-associated protein and induces the activation of ATF6 Virology 2009 387 402 413 10.1016/j.virol.2009.02.021 19304306 PMC7103415

186. Rothan HA Kumar M Role of endoplasmic reticulum-associated proteins in flavivirus replication and assembly complexes Pathogens. 2019 8 3 148 10.3390/pathogens8030148 PMC6789530 31547236

187. Mehta P, Ciurtin C, Scully M, Levi M, Chambers RC. JAK inhibitors in COVID-19: need for vigilance regarding increased inherent thrombotic risk. Eur Respir J. 2020:2001919. doi: 10.1183/13993003.01919-2020. 10.1183/13993003.01919-2020 PMC7338400 32631841

188. La Rosée F Bremer HC Gehrke I Kehr A Hochhaus A Birndt S The Janus kinase 1/2 inhibitor ruxolitinib in COVID-19 with severe systemic hyperinflammation Leukemia 2020 34 1805 1815 10.1038/s41375-020-0891-0 32518419 PMC7282206

189. Cantini F Niccoli L Matarrese D Nicastri E Stobbione P Goletti D Baricitinib therapy in COVID-19: a pilot study on safety and clinical impact J Infect. 2020 81 2 318 356 10.1016/j.jinf.2020.04.017 32333918 PMC7177073

190. Bronte V, Ugel S, Tinazzi E, Vella A, Sanctis FDe, Canè S, et al. Baricitinib restrains the immune dysregulation in COVID-19 patients. Preprint at medRxiv, 10.1101/2020.06.26.20135319.

191. RECOVERY Collaborative Group, Horby P, Lim WS, Emberson JR, Mafham M, Bell JL, et al. Dexamethasone in hospitalized patients with Covid-19 - preliminary report. N Engl J Med. 2020: NEJMoa2021436 doi: 10.1056/NEJMoa2021436.

192. Johnson RM, Vinetz JM. Dexamethasone in the management of covid -19. BMJ 2020; 370. 10.1136/bmj.m2648. 10.1136/bmj.m2648 32620554

193. Theoharides TC, Conti P. Dexamethasone for COVID-19? Not so fast. J Biol Regul Homeost Agents. 2020;34(3). https://doi.org/10.23812/20-EDITORIAL_1–5. 10.23812/20-EDITORIAL_1-5 32551464

194. Brotherton H Usuf E Nadjm B Forrest K Bojang K Samateh AL Dexamethasone for COVID-19: data needed from randomised clinical trials in Africa Lancet Glob Health 2020 10.1016/S2214-109X(20)30318-1 32679038 PMC7833918

195. Li Y, Zhang J, Wang N, Li H, Shi Y, Guo G, et al. Therapeutic drugs targeting 2019-nCoV main protease by high-throughput screening. BioRxiv. Preprint at https://www.biorxiv.org . 10.1101/2020.01.28.922922.

196. Elfiky AA Ribavirin, remdesivir, sofosbuvir, galidesivir, and tenofovir against SARS-CoV-2 RNA dependent RNA polymerase (RdRp): a molecular docking study Life Sci 2020 25 117592 10.1016/j.lfs.2020.117592 PMC7102646 32222463

197. Balasubramaniam M, Reis RS. Computational target-based drug repurposing of elbasvir, an antiviral drug predicted to bind multiple SARS-CoV-2 proteins. ChemRxiv. 10.26434/chemrxiv.12084822.v2.

198. Sargiacomo C Sotgia F Lisanti MP COVID-19 and chronological aging: senolytics and other anti-aging drugs for the treatment or prevention of corona virus infection? Aging (Albany NY) 2020 12 6511 6517 10.18632/aging.103001 32229706 PMC7202514

199. Elfiky AA. SARS-CoV-2 RNA dependent RNA polymerase (RdRp) targeting: an in silico perspective. J Biomol Struct Dyn. 2020;1–9. 10.1080/07391102.2020.1761882. 10.1080/07391102.2020.1761882 PMC7222627 32338164

200. Cai Q Yang M Liu D Experimental treatment with favipiravir for COVID-19: an open-label control study Engineering (Beijing) 2020 10.1016/j.eng.2020.03.007.10.1016/j.eng.2020.03.007 32346491 PMC7185795

201. Chen C, Zhang Y, Huang J, Yin P, Cheng Z, Wu J et al. Favipiravir versus arbidol for COVID-19: a randomized clinical trial. medRxiv. 2020:2020.03.17.20037432.

202. Chen ZR Zhou Y Liu J Peng HW Zhou J Zhong HL Pharmacotherapics advice in guidelines for COVID-19 Front Pharmacol. 2020 11 950 10.3389/fphar.2020.00950 32670066 PMC7327107

203. Wang J Fast identification of possible drug treatment of coronavirus disease-19 (COVID-19) through computational drug repurposing study J Chem Inf Model 2020 60 3277 3286 10.1021/acs.jcim.0c00179 32315171 PMC7197972

204. Ruan Z Liu C Guo Y He Z Huang X Jia X SARS-CoV-2 and SARS-CoV: virtual screening of potential inhibitors targeting RNA-dependent RNA polymerase activity (NSP12) J Med Virol. 2020 10.1002/jmv.26222 32579254 PMC7361265

205. Alméciga-Díaz CJ, Pimentel-Vera LN, Caro A, Mosquera A, Moreno CAC, Rojas JPM, et al. Virtual screening of potential inhibitors for SARS-CoV-2 main protease, (2020). https://www.preprints.org/manuscript/202004.0146/v1 .

206. Ohashi H, Watashi K, Saso W, Shionoya K, Iwanami S, Hirokawa T, et al. Multidrug treatment with nelfinavir and cepharanthine against COVID-19. bioRxiv 2020.04.14.039925; 10.1101/2020.04.14.039925.

207. Sayad B Sobhani M Khodarahmi R Sofosbuvir as repurposed antiviral drug against COVID-19: Why were we convinced to evaluate the drug in a registered/approved clinical trial? Arch Med Res. 2020 S0188–4409 20 30551 30558 10.1016/j.arcmed.2020.04.018 PMC7188631 32387040

208. Chien M, Anderson TK, Jockusch S, Tao C, Kumar S, Li X, et al. Nucleotide Analogues as Inhibitors of SARS-CoV-2 Polymerase. Preprint. bioRxiv. 2020;2020.03.18.997585. Published 2020 Mar 20. doi:10.1101/2020.03.18.997585.

209. Choy KT Wong AY Kaewpreedee P Sia SF Chen D Hui KPY Remdesivir, lopinavir, emetine, and homoharringtonine inhibit SARS-CoV-2 replication in vitro Antiviral Res. 2020 178 104786 10.1016/j.antiviral.2020.104786 32251767 PMC7127386

210. Liu X Wang XJ Potential inhibitors against 2019-nCoV coronavirus M protease from clinically approved medicines J Genet Genomics. 2020 47 2 119 121 10.1016/j.jgg.2020.02.001 32173287 PMC7128649

211. De Meyer S Bojkova D Cinatl J Van Damme E Buyck C Van Loock M Lack of antiviral activity of darunavir against SARS-CoV-2 Int J Infect Dis. 2020 97 7 10 10.1016/j.ijid.2020.05.085 32479865 PMC7258847

212. Vankadari N Arbidol: A potential antiviral drug for the treatment of SARS-CoV-2 by blocking trimerization of the spike glycoprotein Int J Antimicrob Agents. 2020 56 2 105998 10.1016/j.ijantimicag.2020.105998 32360231 PMC7187825

213. Zhu Z Lu Z Xu T Chen C Yang G Zha T Arbidol monotherapy is superior to lopinavir/ritonavir in treating COVID-19 J Infect. 2020 81 e21 e23 10.1016/j.jinf.2020.03.060 32283143 PMC7195393

214. Hoffmann M Schroeder S Kleine-Weber H Müller MA Drosten C Pöhlmann S Nafamostat mesylate blocks activation of SARS-CoV-2: new treatment option for COVID-19 Antimicrob Agents Chemother. 2020 64 e00754 e820 10.1128/AAC.00754-20 32312781 PMC7269515

215. Jang S Rhee JY Three cases of treatment with nafamostat in elderly patients with COVID-19 pneumonia who need oxygen therapy Int J Infect Dis. 2020 S1201–9712 20 30379 30389 10.1016/j.ijid.2020.05.072 PMC7250091 32470602

216. Yao X, Ye F, Zhang M, Cui C, Huang B, Niu P, et al. In Vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Clin Infect Dis. 2020;ciaa237. doi:10.1093/cid/ciaa237. 10.1093/cid/ciaa237 PMC7108130 32150618

217. Encinar JA Menendez JA Potential drugs targeting early innate immune evasion of sars-coronavirus 2 via 2'-O-methylation of viral RNA Viruses 2020 12 525 10.3390/v12050525 PMC7291090 32397643

218. Musarrat F Chouljenko V Dahal A Nabi R Chouljenko T Jois SD The anti-HIV drug nelfinavir mesylate (Viracept) is a potent inhibitor of cell fusion caused by the SARSCoV-2 spike (S) glycoprotein warranting further evaluation as an antiviral against COVID-19 infections J Med Virol. 2020 10.1002/jmv.25985.10.1002/jmv.25985 32374457 PMC7267418

219. Khan RJ, Jha RK, Amera GM, Jain M, Singh E, Pathak A, et al. Targeting SARS-CoV-2: a systematic drug repurposing approach to identify promising inhibitors against 3C-like proteinase and 2'-O-ribose methyltransferase. J Biomol Struct Dyn. 2020;1–14. doi:10.1080/07391102.2020.1753577. 10.1080/07391102.2020.1753577 PMC7189412 32266873

220. Poschet JF, Perkett EA, Timmins GS, Deretic V. Azithromycin and ciprofloxacin have a chloroquine-like effect on respiratory epithelial cells. bioRxiv. 2020;3(29). doi: 10.1101/2020.03.29.008631.

221. Gautret P, Lagier JC, Parola P, Hoang VT, Meddeb L, Mailhe M, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J Antimicrob Agents. 2020;105949. 10.1016/j.ijantimicag.2020.105949. 10.1016/j.ijantimicag.2020.105949 PMC7102549 32205204

222. Marinho EM, Batista de Andrade Neto J, Silva J, Rocha da Silva C, Cavalcanti BC, Marinho ES, et al. Virtual screening based on molecular docking of possible inhibitors of Covid-19 main protease. Microb Pathog. 2020;104365. doi: 10.1016/j.micpath.2020.104365. 10.1016/j.micpath.2020.104365 PMC7834391 32619669

223. Cao Y Wei J Zou L Jiang T Wang G Chen L Ruxolitinib in treatment of severe coronavirus disease 2019 (COVID-19): a multicenter, single-blind, randomized controlled trial J Allergy Clin Immunol. 2020 146 137–146 e3 10.1016/j.jaci.2020.05.019 PMC7250105 32470486

224. Cantini F Niccoli L Nannini C Matarrese D Natale MED Lotti P Beneficial impact of baricitinib in COVID-19 moderate pneumonia; multicentre study J Infect. 2020 S0163–4453 20 30433 30443 10.1016/j.jinf.2020.06.052 PMC7313480 32592703

225. Khan SU, Htar TT. Deciphering the binding mechanism of dexamethasone against SARS-CoV-2 main protease: computational molecular modelling approach. Priprint at ChemRxiv. 23/06/2020. 10.26434/chemrxiv.12517535.v1.

226. Shah B Modi P Sagar SR In silico studies on therapeutic agents for COVID-19: Drug repurposing approach Life Sci. 2020 252 117652 10.1016/j.lfs.2020.117652 32278693 PMC7194845

227. Khater S Das G Repurposing ivermectin to inhibit the activity of SARS CoV2 helicase: possible implications for COVID 19 therapeutics OSF Preprints. 2020 10.31219/osf.io/8dseq

228. Anastasiou IA Eleftheriadou I Tentolouris A Tsilingiris D Tentolouris N In vitro data of current therapies for SARS-CoV-2 Curr Med Chem. 2020 10.2174/0929867327666200513075430.10.2174/0929867327666200513075430 32400323

229. Calderón JM Zerón HM Padmanabhan S Treatment with Hydroxychloroquine vs Hydroxychloroquine + Nitazoxanide in COVID-19 patients with risk factors for poor prognosis: a structured summary of a study protocol for a randomised controlled trial Trials. 2020 21 504 10.1186/s13063-020-04448-2 32513231 PMC7276957