Recent Advances in Molecular Mechanisms of Nucleoside Antivirals

Current Issues in Molecular Biology, Journal Year: 2023, Volume and Issue: 45(8), P. 6851 - 6879

Published: Aug. 17, 2023

The search for new drugs has been greatly accelerated by the emergence of viruses and drug-resistant strains known pathogens. Nucleoside analogues (NAs) are a prospective class antivirals due to safety profiles, which important rapid repurposing in fight against emerging Recent improvements research methods have revealed unexpected details mechanisms action NAs that can pave way approaches further development effective drugs. This review accounts advanced techniques viral polymerase targeting, host enzyme targeting approaches, prodrug-based strategies antiviral NAs.

Language: Английский

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Synergism between remdesivir and ribavirin leads to SARS‐CoV‐2 extinction in cell culture

British Journal of Pharmacology, Journal Year: 2024, Volume and Issue: 181(15), P. 2636 - 2654

Published: April 14, 2024

There is a need for effective anti-COVID-19 treatments, mainly individuals at risk of severe disease such as the elderly and immunosuppressed. Drug repositioning has proved in identifying drugs that can find new application control coronavirus disease, particular COVID-19. The purpose present study was to synergistic antiviral combinations COVID-19 based on lethal mutagenesis.

Language: Английский

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Small Molecule Drugs Targeting Viral Polymerases

Pharmaceuticals, Journal Year: 2024, Volume and Issue: 17(5), P. 661 - 661

Published: May 20, 2024

Small molecules that specifically target viral polymerases—crucial enzymes governing genome transcription and replication—play a pivotal role in combating infections. Presently, approved polymerase inhibitors cover nine human viruses, spanning both DNA RNA viruses. This review provides comprehensive analysis of these licensed drugs, encompassing nucleoside/nucleotide (NIs), non-nucleoside (NNIs), mutagenic agents. For each compound, we describe the specific targeted virus related enzyme, mechanism action, relevant bioactivity data. wealth information serves as valuable resource for researchers actively engaged antiviral drug discovery efforts, offering complete overview established strategies well insights shaping development next-generation therapeutics.

Language: Английский

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Structure-Based Drug Design of RdRp Inhibitors against SARS-CoV-2

Topics in Current Chemistry, Journal Year: 2023, Volume and Issue: 381(5)

Published: June 15, 2023

Language: Английский

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Effectiveness of nucleoside analogs against Wetland virus infection

Antiviral Research, Journal Year: 2025, Volume and Issue: unknown, P. 106114 - 106114

Published: Feb. 1, 2025

Language: Английский

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Antivirals in COVID‐19: A Focus on Pediatric Cardiac Patients

Canadian Journal of Infectious Diseases and Medical Microbiology, Journal Year: 2025, Volume and Issue: 2025(1)

Published: Jan. 1, 2025

The COVID‐19 pandemic created an unprecedented public health crisis, driven by its rapid global spread and the urgent need for worldwide collaborative interventions to contain it. This urgency spurred search therapeutic agents prevent or manage infection. Among these, various types of antivirals emerged as a prominent treatment option, supported wealth observational studies randomized controlled trials. results from such conflict, with some concluding efficacy others lack thereof, variability also occurring depending on severity in studied population. In addition, many have been explored using trials—the gold standard evaluating intervention—to only limited degree, most evidence behind their use concluded studies. Thus, sheer volume data has made it challenging resolve inconsistencies determine true efficacy. Furthermore, there is paucity literature regarding pediatric population infected COVID‐19, being extrapolated done adult patients. As such, additional trials are needed solidify effectiveness managing particularly underexplored especially vulnerable cardiac Therefore, utilizing trials, this narrative review evaluates rationale antivirals, summarizes findings literature, concludes focused discussion application

Language: Английский

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Antiviral therapies for the management of persistent coronavirus disease 2019 in immunocompromised hosts: A narrative review

Transplant Infectious Disease, Journal Year: 2024, Volume and Issue: 26(3)

Published: May 29, 2024

Abstract Antiviral agents with activity against severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) have played a critical role in disease management; however, little is known regarding the efficacy of these medications treatment SARS‐CoV‐2 infection immunocompromised patients, particularly management persistent positivity. This narrative review discusses 2019 hosts, focus on antiviral therapies. We identified 84 cases from literature describing variety approaches, including prolonged therapy ( n = 11), combination antivirals 13), and mixed antibody treatments 60). A high proportion had an underlying haematologic malignancy 67, 80%), were receipt anti‐CD20 51, 60%). Success was reported 70 (83%) which varied according to type. Combination therapies may be effective approach for individuals positivity, those that incorporate aimed at increasing neutralizing levels. Any novel approaches taken this difficult dilemma should mindful emergence resistance.

Language: Английский

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The activation cascade of the broad-spectrum antiviral bemnifosbuvir characterized at atomic resolution

PLoS Biology, Journal Year: 2024, Volume and Issue: 22(8), P. e3002743 - e3002743

Published: Aug. 27, 2024

Bemnifosbuvir (AT-527) and AT-752 are guanosine analogues currently in clinical trials against several RNA viruses. Here, we show that these drugs require a minimal set of 5 cellular enzymes for activation to their common 5′-triphosphate AT-9010, with an obligate order reactions. AT-9010 selectively inhibits essential viral enzymes, accounting antiviral potency. Functional structural data at atomic resolution decipher N 6 -purine deamination compatible its metabolic activation. Crystal structures human histidine triad nucleotide binding protein 1, adenosine deaminase-like guanylate kinase nucleoside diphosphate 2.09, 2.44, 1.76, 1.9 Å resolution, respectively, cognate precursors illuminate the pathway from orally available bemnifosbuvir pointing key drug–protein contacts along pathway. Our work provides framework integrate design analogues, confronting requirements constraints associated assembly line.

Language: Английский

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Transient SARS-CoV-2 RNA-Dependent RNA Polymerase Mutations after Remdesivir Treatment for Chronic COVID-19 in Two Transplant Recipients: Case Report and Intra-Host Viral Genomic Investigation

Microorganisms, Journal Year: 2023, Volume and Issue: 11(8), P. 2096 - 2096

Published: Aug. 16, 2023

Remdesivir is the first FDA-approved drug for treating severe SARS-CoV-2 infection and targets RNA-dependent RNA polymerase (RdRp) that required viral replication. To monitor development of mutations may result in remdesivir resistance during prolonged treatment, we sequenced specimens collected at different treatment time points two transplant patients with COVID-19. In patient, an allogeneic hematopoietic stem cell recipient, a transient RdRp catalytic subunit mutation (nsp12:A449V) was observed has not previously been associated resistance. As no vitro study had conducted to elucidate phenotypic effect nsp12:A449V, its clinical significance unclear. second other were detected: one (nsp12:V166A) accessory important processivity (nsp7:D67N). This case report potential link between nsp12:V166A vivo, which only described by studies. The nsp7:D67N resistance, whether it unknown. Our revealed genetic dynamics recipients involved complex (nsp7 nsp12), be selective pressure. These results suggest close monitoring course highly vulnerable patient populations beneficial. Development utilization diagnostic genotyping tests future direction improving management chronic

Language: Английский

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Elucidating the Role of Noncovalent Interactions in Favipiravir, a Drug Active against Various Human RNA Viruses; a 1H-14N NQDR/Periodic DFT/QTAIM/RDS/3D Hirshfeld Surfaces Combined Study

Molecules, Journal Year: 2023, Volume and Issue: 28(8), P. 3308 - 3308

Published: April 7, 2023

Favipiravir (6-fluoro-3-hydroxypyrazine-2-carboxamide, FPV), an active pharmaceutical component of the drug discovered and registered in March 2014 Japan under name Avigan, with indication for pandemic influenza, has been studied. The study this compound was prompted by idea that effective processes recognition binding FPV to nucleic acid are affected predominantly propensity form intra- intermolecular interactions. Three nuclear quadrupole resonance experimental techniques, namely 1H-14N cross-relaxation, multiple frequency sweeps, two-frequency irradiation, followed solid-state computational modelling (density functional theory supplemented quantum atoms molecules, 3D Hirshfeld Surfaces, reduced density gradient) approaches were applied. complete NQR spectrum consisting nine lines indicating presence three chemically inequivalent nitrogen sites molecule detected, assignment particular performed. description nearest vicinity all used characterize nature interactions from perspective local single draw some conclusions on required binding. electrostatic N-H···O, N-H···N, C-H···O hydrogen bonds competitive two intramolecular bonds, strong O-H···O very weak closing 5-member ring stiffening structure, as well π···π F···F dispersive interactions, analysed detail. hypothesis regarding similarity interaction pattern solid RNA template verified. It -NH2 group crystal participates N-H···N precatalytic state only while N-H···O which is importance link FVP template. Our elucidates modes (in crystal, precatalytic, forms) detail should guide design more potent analogues targeting SARS-CoV-2. Strong direct FVP-RTP both site cofactor us suggests a possible alternative, allosteric mechanism action, may explain scattering results clinical trials or synergistic effect observed combined treatment against

Language: Английский

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