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Targeting the conserved RNA-dependent RNA polymerase with antisense oligonucleotides suppresses SARS-CoV-2 variants.

The rapid evolution of Severe Acute Respiratory Syndrome Coronavirus 2(SARS-CoV-2) variants, particularly mutations in the spike protein, has compromised the efficacy of many therapeutics, highlighting the urgent need for broad-spectrum antiviral strategies. The RNA-dependent RNA polymerase (RdRp), a core enzyme essential for viral replication and transcription, represents an ideal target due to its high sequence conservation across SARS-CoV-2 variants and related coronaviruses, as well as its functional indispensability-mutations in its catalytic core typically incur significant viral fitness…

Structural and functional characterisation of the Crimean-Congo haemorrhagic fever virus RNA dependent RNA polymerase.

Crimean-Congo Haemorrhagic Fever Virus (CCHFV) is found across Africa, Asia, and the Middle East where it can cause Haemorrhagic outbreaks with high case fatality rates. Central to the viral life cycle is the viral L-protein, a crucial and multifunctional protein which both transcribes and replicates the viral genome. Here, we present the cryoEM structures of an RNA free and a 5' promoter bound complex, describing the core catalytic RNA-dependent RNA polymerase (RdRp). We observe an RdRp that is substantially larger than related L-proteins and contains domain insertions unique to the nairoviru…

Allosteric Inhibitors of SARS-CoV-2 RNA-Dependent RNA Polymerase Based on N,N'-Diphenylurea.

The COVID-19 pandemic, caused by the highly transmissible SARS-CoV-2 virus, has highlighted the urgent need for effective small-molecule antivirals. To date, only a few such agents, including molnupiravir and remdesivir, have been approved by the FDA. In our previous study, a novel class of SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) inhibitors based on an N,N'-diphenylurea scaffold was identified; however, these compounds exhibited poor aqueous solubility and significant cytotoxicity. Herein, the design, synthesis, and evaluation of twenty-seven new derivatives aimed at improving solubilit…

Discovery of a Novel Non-Nucleoside Inhibitor of RNA-Dependent RNA Polymerase Against Dengue Virus.

Dengue virus (DENV) is an acute infectious pathogen worldwide, for which no effective therapeutics are available. The RNA-dependent RNA polymerase (RdRp) displays an important role during DENV replication and is therefore a promising target in the development of antiviral drugs. However, there are still no clinically approved RdRp inhibitors available. In this study, we identified a natural small molecule, 12β-hydroxydammar-3-one-20(S)-O-β-d-glucopyranoside (PN-1), using a surface plasmon resonance-based screening assay. Biochemical and structural analyses revealed that PN-1 selectively target…

A cell-based assay to discover inhibitors of SARS-CoV-2 RNA dependent RNA polymerase.

Antiviral therapeutics is one effective avenue to control and end this devastating COVID-19 pandemic. The viral RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2 has been recognized as a valuable target of antivirals. However, the cell-free SARS-CoV-2 RdRp biochemical assay requires the conversion of nucleotide prodrugs into the active triphosphate forms, which regularly occurs in cells yet is a complicated multiple-step chemical process in vitro, and thus hinders the utility of this cell-free assay in the rapid discovery of RdRp inhibitors. In addition, SARS-CoV-2 exoribonuclease provides the…

Repurposing nonnucleoside antivirals against SARS-CoV2 NSP12 (RNA dependent RNA polymerase): In silico-molecular insight.

The pandemic of SARS-CoV-2 has necessitated expedited research efforts towards finding potential antiviral targets and drug development measures. While new drug discovery is time consuming, drug repurposing has been a promising area for elaborate virtual screening and identification of existing FDA approved drugs that could possibly be used for targeting against functions of various proteins of SARS-CoV-2 virus. RNA dependent RNA polymerase (RdRp) is an important enzyme for the virus that mediates replication of the viral RNA. Inhibition of RdRp could inhibit viral RNA replication and thus new

Recent advances in the discovery of potent RNA-dependent RNA-polymerase (RdRp) inhibitors targeting viruses.

WHO has declared COVID-19 a pandemic, which has affected the whole world and has caused unprecedented social and economic disruption. Since the emergence of the disease, several druggable targets have been suggested including 3-chymotrypsin-like protease (3CLpro), spike, RNA-dependent RNA polymerase (RdRp), and the papain-like protease (PLpro) computational approach. From the beginning, viral replication has been the main focus for any antiviral drug development for viral diseases, including HCV, influenza virus, zika virus, norovirus, measles, dengue virus, and coronaviruses. This review list…

Role of Enteroviral RNA-Dependent RNA Polymerase in Regulation of MDA5-Mediated Beta Interferon Activation.

Infection by enteroviruses can cause severe neurological complications in humans. The interactions between the enteroviral and host proteins … for initiating transcription of type I interferons. In the present study, we demonstrated that the RNA-dependent RNA polymerase (RdRP; also denoted 3Dpol) encoded by EV71 interacts with the caspase activation and recruitment domains (CARDs) of MDA5 and plays a role in the inhibition of MDA5-mediated beta interferon (IFN-β) promoter activation and mRNA expression. In addition …

Differential expression of cucumber RNA-dependent RNA polymerase 1 genes during antiviral defence and resistance.

RNA-dependent RNA polymerase 1 (RDR1) plays a crucial role in plant defence against viruses. In this study, it was observed that cucumber, Cucumis sativus, uniquely encodes a small gene family of four RDR1 genes. The cucumber RDR1 genes (CsRDR1a, CsRDR1b and duplicated CsRDR1c1/c2) shared 55%-60% homology in their encoded amino acid sequences. In healthy cucumber plants, RDR1a and RDR1b transcripts were expressed at higher levels than transcripts of RDR1c1/c2, which were barely detectable. The expression of all four CsRDR1 genes was induced by virus infection, after which the expression level …

The nucleoside analog CMX521 inhibits coronavirus RNA-dependent RNA polymerase via a two-pronged mechanism.

The SARS-CoV-2 pandemic has underscored the urgent need for broad-spectrum antivirals in pandemic preparedness efforts. Nucleoside analogs targeting viral polymerases are often considered in this context. Here, we employ ensemble biochemical assays and single-molecule magnetic tweezers to characterize the detailed mechanism of action of the adenosine analog CMX521 (developed through Phase 1 clinical studies), a broad-spectrum antiviral against caliciviruses and coronaviruses, against SARS-CoV-2 RNA-dependent RNA polymerase (RdRp). The triphosphate form of CMX521 is efficiently incorporated by …

The nucleoside analog CMX521 inhibits coronavirus RNA-dependent RNA polymerase via a two-pronged mechanism.

The SARS-CoV-2 pandemic has underscored the urgent need for broad-spectrum antivirals in pandemic preparedness efforts. Nucleoside analogs targeting viral polymerases are often considered in this context. Here, we employ ensemble biochemical assays and single-molecule magnetic tweezers to characterize the detailed mechanism of action of the adenosine analog CMX521 (developed through Phase 1 clinical studies), a broad-spectrum antiviral against caliciviruses and coronaviruses, against SARS-CoV-2 RNA-dependent RNA polymerase (RdRp). The triphosphate form of CMX521 is efficiently incorporated by …

Licoflavone B Suppresses Influenza A Virus by Targeting the Viral RNA-Dependent RNA Polymerase (RdRp).

Influenza A virus pandemics pose a persistent global health threat, and emerging antiviral resistance underscores the critical importance of … pes and type B virus. Mechanistic studies revealed that licoflavone B selectively targets the viral RNA-dependent RNA polymerase (RdRp), effectively suppressing viral replication. The compound exhibits a favorable selectivity index (SI = 14.9-29.9), indicating a promising therapeutic window. Molecular docking simulations identified potential binding interactions between licof …

The neddylation of the RNA-dependent RNA polymerase 3D of Coxsackievirus B3 promotes viral replication.

The pathogenesis of Coxsackievirus B3 (CVB3), the causative pathogen for severe diseases such as myocarditis, pancreatitis, and meningitis, remains largely unknown. Neddylation, the covalent modification of proteins through the conjugation of NEDD8, a ubiquitin-like molecule, plays critical roles in regulating cellular activities. Our previous study demonstrated that 3Dpol, the RNA-dependent RNA polymerase of CVB3, was modified by ubiquitin. Since NEDD8 is highly homologous to ubiquitin in both the sequence and structure, we hypothesized that 3Dpol may also undergo neddylation. Here, we demons…

Zingiberaceae-derived phytomolecules inhibit Japanese encephalitis virus RNA dependent RNA polymerase: a molecular dynamics study.

The Japanese encephalitis virus, (JEV), is a flavivirus mostly transmitted by Culex mosquitoes mostly present in Southeast Asia and the Western Pacific region. Ardeid-wading birds are the natural reservoir of JEV; nonetheless, pigs are frequently a key amplifying host during epidemics in human populations. Although more domestic animals and wildlife are JEV hosts, it is unclear how these animals fit into the ecology and epidemiology of the virus. Even though there is no specific therapy, vaccines are available to prevent this infection. However, current vaccinations do not work against every c

Tiratricol inhibits yellow fever virus replication through targeting viral RNA-dependent RNA polymerase of NS5.

Yellow fever virus (YFV) infection is a major public concern that threatens a large population in South America and Africa. No specific anti … ssay and molecular docking analysis indicate that TRIAC hinders viral replication by binding to the RNA-dependent RNA polymerase (RdRp) domain of viral nonstructural protein NS5, probably through interacting with the active sites of RdRp.The inhibitory effect of TRIAC in vivo is also confirmed in 3-week old C57BL/6 mice challenged with YFV infection, from which the survival o …

Discovery of non-nucleoside oxindole derivatives as potent inhibitors against dengue RNA-dependent RNA polymerase.

A series of thiazole linked Oxindole-5-Sulfonamide (OSA) derivatives were designed as inhibitors of RNA-dependent RNA polymerase (RdRp) activity of Dengue virus. These were synthesized and then evaluated for their efficacy in ex-vivo virus replication assay using human cell lines. Among 20 primary compounds in the series, OSA-15 was identified as a hit. A series of analogues were synthesized by replacing the difluoro benzyl group of OSA-15 with different substituted benzyl groups. The efficacy of OSA-15derivatives was less than that of the parent compound, except OSA-15-17, which has shown imp…

Коэффициент внутримолекулярного инициирования на основе конформации, определяемый в полимеразе Флавируса РНК, зависящей от РНК.

Флавивирусы создают серьезную угрозу для здоровья человека. Будучи естественным синтезом метилпереносазы (Мтазы) и зависящей от РНК полимеразы (RDRP), NS5 является наиболее консервированным флавивирусным белком и важной антивирусной целью. Ранее сообщалось о том, что структуры NS5, представленные японскими вирусами энцефалита (JEV) и серотипом 3 вируса Денге (DENV3), имеют две явно различные глобальные конформации, определяющие два набора внутримолекулярных взаимодействия MTase-RdRP. Вместе с тем, сохраняются ли эти конформации NS5 в флавивирусах, и их специфические функции по-прежнему остаютс

Совпадение в аннотации оригинала
The flaviviruses pose serious threats to human health. Being a natural fusion of a methyltransferase (MTase) and an RNA-dependent RNA polymerase (RdRP), NS5 is the most conserved flavivirus protein and an important antiviral target. Previously reported NS5 structures represented by those from the Japanese encephalitis virus (JEV) and Dengue virus serotype 3 …

Endogenous grouper and barramundi Mx proteins facilitated the clearance of betanodavirus RNA-dependent RNA polymerase.

This study confirmed that the infection of nervous necrosis virus (NNV), belonging to the betanodavirus, can induce the expression of endogenous Mx in grouper fin-3 (GF-3), grouper brain (cGB), and barramundi brain (cBB) cells, but not in grouper fin-1 (GF-1) cells. In a co-sedimentation assay, RdRp appeared in the mitochondrial pellet of GF-1 cells without endogenous Mx expression. However, in GF-3, cGB, and cBB cells, RdRp was detected in the nuclear pellet accompanied by endogenous Mx. By immunostaining, RdRp was found to colocalize with not only endogenous Mx but also lysosomes and monodan

Identification of a Pyridoxine-Derived Small-Molecule Inhibitor Targeting Dengue Virus RNA-Dependent RNA Polymerase.

The viral RNA-dependent RNA polymerase (RdRp) activity of the dengue virus (DENV) NS5 protein is an attractive target for drug design. Here, we report the identification of a novel class of inhibitor (i.e., an active-site metal ion chelator) that acts against DENV RdRp activity. DENV RdRp utilizes a two-metal-ion mechanism of catalysis; therefore, we constructed a small library of compounds, through mechanism-based drug design, aimed at chelating divalent metal ions in the catalytic site of DENV RdRp. We now describe a pyridoxine-derived small-molecule inhibitor that targets DENV RdRp and show…

BPR-3P0128 inhibits RNA-dependent RNA polymerase elongation and VPg uridylylation activities of Enterovirus 71.

Enterovirus 71 (EV71) infections can cause hand, foot, and mouth disease with severe neurological complications. Because no clinical drug is available for treating EV71 infections, developing an efficient antiviral medication against EV71 infection is crucial. This study indicated that 6-bromo-2-[1-(2,5-dimethylphenyl)-5-methyl-1H-pyrazol-4-yl] quinoline-4-carboxylic acid (BPR-3P0128) exhibits excellent antiviral activity against EV71 (EC50 = 0.0029 μM). BPR-3P0128 inhibits viral replication during the early post infection stage, targets EV71 RNA-dependent RNA polymerase and VPg uridylylation,…