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Halogen-Dance-Based Synthesis of Phosphonomethoxyethyl (PME) Substituted 2-Aminothiazoles as Potent Inhibitors of Bacterial Adenylate Cyclases.

A series of acyclic nucleoside phosphonates (ANPs) was designed as inhibitors of bacterial adenylate cyclases (ACs), where adenine was replaced with 2-amino-4-arylthiazoles. The target compounds were prepared using the halogen dance reaction. Final AC inhibitors were evaluated in cell-based assays (prodrugs) and cell-free assays (phosphono diphosphates). Novel ANPs were potent inhibitors of adenylate cyclase toxin (ACT) from Bordetella pertussis and edema factor (EF) from Bacillus anthracis, with substantial selectivity over mammalian enzymes AC1, AC2, and AC5. Six of the new ANPs were more po…

Cladribine and Fludarabine Nucleotides Induce Distinct Hexamers Defining a Common Mode of Reversible RNR Inhibition.

The enzyme ribonucleotide reductase (RNR) is a major target of anticancer drugs. Until recently, suicide inactivation in which synthetic substrate analogs (nucleoside diphosphates) irreversibly inactivate the RNR-α2β2 heterodimeric complex was the only clinically proven inhibition pathway. For instance, this mechanism is deployed by the multifactorial anticancer agent gemcitabine diphosphate. Recently reversible targeting of RNR-α-alone coupled with ligand-induced RNR-α-persistent hexamerization has emerged to be of clinical significance. To date, clofarabine nucleotides are the only known exa…

Design and Synthesis of Fluorescent Acyclic Nucleoside Phosphonates as Potent Inhibitors of Bacterial Adenylate Cyclases.

Bordetella pertussis adenylate cyclase toxin (ACT) and Bacillus anthracis edema factor (EF) are key virulence factors with adenylate cyclase … ed acyclic nucleoside phosphonates (Cl-ANT-ANPs) were designed and synthesized in the form of their diphosphates (Cl-ANT-ANPpp) as competitive ACT and EF inhibitors with sub-micromolar potency (IC50 values: 11-622 nm). Fluorescence experiments indicated that Cl-ANT-ANPpp analogues bind to the ACT active site, and docking studies suggested that the Cl-ANT group …

3' processing of tRNA precursors in ribonuclease-deficient Escherichia coli. Development and characterization of an in vitro processing system and evidence for a phosphate requirement.

In order to determine the mechanism and enzyme(s) responsible for 3' processing of tRNA precursors, we have developed an in vitro processing … n be restored to normal by the addition of inorganic phosphate or arsenate. Furthermore, nucleoside diphosphates are a product of the processing reaction. These data indicate that 3' processing in RNase-deficient extracts involves a phosphorolytic reaction. On the other hand, phosphate is not required for processing in RNase+ extracts, although it does aid in …

Synergistic Activity between Statins and Bisphosphonates against Acute Experimental Toxoplasmosis.

Bisphosphonates are widely used for the treatment of bone disorders. These drugs also inhibit the growth of a variety of protozoan parasites, such as Toxoplasma gondii, the etiologic agent of toxoplasmosis. The target of the most potent bisphosphonates is the isoprenoid biosynthesis pathway enzyme farnesyl diphosphate synthase (FPPS). Based on our previous work on the inhibitory effect of sulfur-containing linear bisphosphonates against T. gondii, we investigated the potential synergistic interaction between one of these derivatives, 1-[(n-heptylthio)ethyl]-1,1-bisphosphonate (C7S), and statin

Consequences of Ca2+ deficiency on macromolecular synthesis and adenylate energy charge in Yersinia pestis.

A 37 but not 26 degrees C virulent Yersinia pestis is known to require at least 2.5 mM Ca2+ for growth; this requirement is potentiated by Mg2+. After shift of log-phase cells (doubling time of 2 h) from 26 to 37 degrees C in Ca2+-deficient medium, shutoff of net ribonucleic acid synthesis preceded that of protein and cell mass. With 2.5 mM Mg2+, about two doublings in cell mass and number occurred before restriction with synthesis of sufficient deoxyribonucleic acid to account for initiation and termination of two postshift rounds of chromosome replication. Temperature shift with 20 mMMg2+ re

Glycosylation in vitro of Semliki-Forest-virus and influenza-virus glycoproteins and its suppression by nucleotide-2-deoxy-hexose.

Cell-free enzyme preparations from cultured fibroblasts infected with Semliki forest virus or fowl plague virus (an influenza A virus) incorporate [14C]-mannose into dolichol-phosphate-mannose, lipid-linked oligosaccharides and into endogenous virus-specific glycoproteins. When GDP-2-deoxy-D-[14C]glucose serves as substrate 2-deoxy-D-[14C]glucose is transferred to dolichol phosphate yielding dolichol-monophosphate-2-deoxy-D-[14C]glucose. UDP-2-deoxy-D-[14C]glucose gives rise also to a lipid which, however, is not a polyprenol derivative. The transfer of [14C]mannose to lipid-extractable fracti

ADP and glucose as possible synergistic partners in the stimulation of liver glycogen synthase activation.

Glucose administered either intravenously or orally causes liver glycogen synthase activation independent of a rise in circulating insulin. … esence of caffeine or ADP was comparable. The effect of ADP was specific among the major nucleoside diphosphates. However, the A0.5 for ADP was greater than the normal liver concentration which does not change in response to either glucose or insulin administration. The effect of ADP appeared distinct from that of the methylxanthines since it was observed that …

Кристальная структура и каталитический механизм дрименоловой синтазы, необычная двухфункциональная терпеновая киклаза-фосфатаза.

Дрименол синтаза из Aquimarina pongiae (ASDMS) — очень необычная химера, интегрирующая two - отдельные, последовательные операции по переработке изопреноидов в рамках единой полипептидной цепи. ASDMS катализирует циклизацию фарнесилового дифосфата (FPP) класса II для образования дрименилового дифосфата, который затем подвергается гидролизу энзим-катализу для получения дрименинола, биоактивного сескитерпенового спирта с антифунгальными и антираковыми свойствами. Здесь мы сообщаем рентгеновские кристаллы ASDMS и его комплекс с сескитерпен тиол. Структура ASDMS имеет дидомаиновую архитектуру, сос

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… Strikingly, the vast number of terpenoid natural products belies their roots in two simple five-carbon precursors, dimethylallyl diphosphate and isopentenyl diphosphate, which are linked together by prenyltransferases to generate linear isoprenoid diphosphates such as C 15 farnesyl diphosphate (FPP) … or C 20 geranylgeranyl diphosphate (GGPP) ( 9 , 10 ). …

An in silico structural insights into Plasmodium LytB protein and its inhibition.

In most of the pathogenic organisms including Plasmodium falciparum, isoprenoids are synthesized via MEP (MethylErythritol 4-Phosphate) pathway. LytB is the last enzyme of this pathway which catalyzes the conversion of (E)-4-hydroxy-3-methylbut-2-en-1-yl diphosphate (HMBPP) into the two isoprenoid precursors: isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP). Since the MEP pathway is not used by humans, it represents an attractive target for the development of new anti-malarial compounds or inhibitors. Here a systematic in silico study has been conducted to get an insight int

The concentration of thiamin and thiamin phosphate esters in patients with alcoholic liver cirrhosis.

The blood and plasma concentrations of thiamin and thiamin phosphate esters were determined concomitantly by high-performance liquid chromatography (HPLC) in 22 patients with alcoholic liver cirrhosis, and also in 10 of them 24 hr after a 100 mg thiamin i.m. injection. Sixteen patients were abstaining from alcohol at the time of the study, 6 were currently misusing alcohol. The control group included 30 healthy volunteers, of whom 10 were given the same thiamin injection as the patients. Blood thiamin diphosphate was the only compound decreased in the abstaining patients compared to controls (

Resolving Blocked Antigen Phenomenon in Hemolytic Disease of the Fetus and Newborn Due to Anti-K.

High-titer antibodies are a cause of false-negative reactions in red blood cell antigen phenotyping, an event referred to as blocked antigen phenomenon (BAP). In hemolytic disease of the fetus and newborn, BAP complicates laboratory workups as fetal phenotype is helpful in confirming the responsible antibody. Acid elution techniques, techniques using ethylenediaminetetraacetic glycine acid, as well as those using chloroquine diphosphate have been used to resolve BAP; however, ethylenediaminetetraacetic glycine acid destroys K-antigen expression and chloroquine diphosphate is not always effecti

Isolation of Sporothrix schenckii GDA1 and functional characterization of the encoded guanosine diphosphatase activity.

Sporothrix schenckii is a fungal pathogen of humans and the etiological agent of sporotrichosis. In fungi, proper protein glycosylation is usually required for normal composition of cell wall and virulence. Upon addition of precursor oligosaccharides to nascent proteins in the endoplasmic reticulum, glycans are further modified by Golgi-glycosyl transferases. In order to add sugar residues to precursor glycans, nucleotide diphosphate sugars are imported from the cytosol to the Golgi lumen, the sugar is transferred to glycans, and the resulting nucleoside diphosphate is dephosphorylated by the

Hypotensive effect of UDP on intraocular pressure in rabbits.

Nucleotides can modify intraocular pressure (IOP). We have tested the ability of uridine-5'-diphosphate, UDP, for modulating IOP in New Zealand white rabbits. Uridine 5' diphosphate, UDP, reduced IOP by 82.9+/-2.6% compared to control. Dose-response analysis demonstrated a concentration dependent pattern which presented a pD(2) value of 7.57+/-1.45, equivalent to an EC(50) of 26.91 nM. Of all the tested P2 receptor antagonists, suramin, pyridoxalphosphate-6-azophenyl-2, 4-disulfonic acid (PPADS) and Reactive Blue 2 (RB-2), only the last two were able to reverse the action triggered by UDP. Alt

High-energy phosphate levels in the cerebral artery during chronic vasospasm after subarachnoid hemorrhage.

High-energy phosphate levels were measured in the canine cerebral artery during chronic vasospasm. Subarachnoid hemorrhage and vasospasm were induced by percutaneous injections of autologous venous blood into the cisterna magna. Narrowing of the artery was confirmed by angiography 7 days later. Levels of adenosine phosphates (adenosine triphosphate (ATP), adenosine diphosphate (ADP), and adenosine monophosphate (AMP)), guanosine phosphates (guanosine triphosphate (GTP) and guanosine diphosphate (GDP)), and creatine phosphate (CrP) in the basilar artery were quantified using high-performance li

Phenothiazine compounds enhance phentolamine effects on platelet aggregation and thromboxane B2 production.

In the present study we investigated the influence of phentolamine and the phenothiazine compounds chlorpromazine and trifluoperazine on human platelet aggregation as well as the effect of the association of phentolamine and the phenothiazines on responses to adenosine diphosphate, collagen, thrombin, ionophore A23187 and phorbol-myristate acetate, release reaction, thromboxane B2 synthesis and intraplatelet cyclic adenosine monophosphate levels. Phentolamine and phenothiazines exerted a dose-dependent inhibitory effect on aggregation induced by different concentrations of adenosine diphosphat

The impact of and changes in the oxidative status in the post-injury period following nonpenetrating traumatic brain injuries.

ObjectiveIn the pathogenesis of the post-injury period following nonpenetrating traumatic brain injuries (TBIs; post-TBIs), pathological metabolic changes in the oxidative status are important, as a complete understanding of their interactions can explain the concept of how oxidative metabolic-related differences develop, thereby supporting effective treatment.MethodsThis case-control study included 63 patients (mean age ± SD, 36.19 ± 11.4 years) in the post-TBI group and 32 healthy controls. Participants were tested for creatine kinase, adenosine triphosphate, and adenosine diphosphate levels

Biosynthesis of mercapturic acid derivative of the labdane-type diterpene, cyslabdan that potentiates imipenem activity against methicillin-resistant Staphylococcus aureus: cyslabdan is generated by mycothiol-mediated xenobiotic detoxification.

Genome mining of cyslabdan-producing Streptomyces cyslabdanicus K04-0144 revealed that a set of four genes, cldA, cldB, cldC, and cldD (the cld cluster), which formed a single transcriptional unit, were involved in the biosynthesis of cyslabdan that potentiates imipenem activity against methicillin-resistant Staphylococcus aureus. Experimental studies supported the heterologous expression of the cld cluster of S. cyslabdanicus K04-0144 in S. avermitilis SUKA22, and transformants carrying the cld cluster produced not only cyslabdan A (1), but also its new derivatives, 17-hydroxyl-1 (2) and 2-hy

Development of a Semi-Mechanistic Population Pharmacokinetic Model for Predicting Tenofovir Disoproxil Fumarate and Tenofovir Alafenamide Exposure in Plasma and Cellular Matrices During Pregnancy and Postpartum.

BACKGROUND AND OBJECTIVE: Tenofovir (TFV)-based regimens are backbones of both HIV treatment and pre-exposure prophylaxis during pregnancy. Multiple studies have shown up to one-third decreases in dried blood spot tenofovir-diphosphate concentrations during pregnancy among participants taking tenofovir disoproxil fumarate (TDF). Currently, there are no mechanism-based models describing the pharmacokinetics of tenofovir diphosphate (the active anabolite) in peripheral blood mononuclear cells (PBMCs) of pregnant individuals receiving TDF or tenofovir alafenamide (TAF), and the mechanisms behind