Atypical Mutational Spectrum of SARS-CoV-2 Replicating in the Presence of Ribavirin

Antimicrobial Agents and Chemotherapy, Год журнала: 2023, Номер 67(1)

Опубликована: Янв. 5, 2023

We report that ribavirin exerts an inhibitory and mutagenic activity on SARS-CoV-2-infecting Vero cells, with a therapeutic index higher than 10. Deep sequencing analysis of the mutant spectrum SARS-CoV-2 replicating in absence or presence indicated increase number mutations, but not deletions, modification diversity indices, expected from activity.

Язык: Английский

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Designing an Efficient Biocatalyst for the Phosphoribosylation of Antiviral Pyrazine-2-carboxamide Derivatives

ACS Catalysis, Год журнала: 2024, Номер 14(5), С. 3687 - 3699

Опубликована: Фев. 21, 2024

The development of technologies for the efficient synthesis innovative antiviral compounds remains an important challenge modern biotechnology, especially in context recent COVID-19 pandemic. One drugs that is currently research spotlight potential anti-SARS-CoV-2 activity purine mimetic prodrug compound T-705, also known as favipiravir. Along with a similar compound, T-1105, activation T-705 limited by low rate phosphoribosylation, mediated enzyme named hypoxanthine-guanine phosphoribosyltransferase (HGPRT). Therefore, phosphoribosylated/ribosylated derivatives these prodrugs viable direction discovery and pharmaceuticals. However, chemical such complex laborious process, whereas enzymatic cascades are not feasible because narrow HGPRT substrate specificity. Here, we report successful rational design biocatalyst T-705/T-1105 phosphoribosylation. With two rounds Thermus thermophilus HB27 active site optimization, have achieved 325-fold increase kcat toward 125-fold T-1105 accompanied multifold decrease KM. practical applicability designed mutant was illustrated through preparative nucleotide derivatives. Our engineered can become basis chemoenzymatic various proven activity. Moreover, our results provide insight into molecular mechanism including experimental evidence explaining reasons behind compounds.

Язык: Английский

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A Tale of Two Drugs: Molnupiravir and Paxlovid

Mutation Research/Reviews in Mutation Research, Год журнала: 2025, Номер 795, С. 108533 - 108533

Опубликована: Янв. 1, 2025

Язык: Английский

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Natural and Designed Cyclic Peptides as Potential Antiviral Drugs to Combat Future Coronavirus Outbreaks

Molecules, Год журнала: 2025, Номер 30(8), С. 1651 - 1651

Опубликована: Апрель 8, 2025

The COVID-19 pandemic has underscored the need for effective and affordable antiviral drugs. Anthropogenic activities have increased interactions among humans, animals, wildlife, contributing to emergence of new re-emerging viral diseases. RNA viruses pose significant challenges due their rapid mutation rates, high transmissibility, ability adapt host immune responses treatments. World Health Organization identified several diseases (COVID-19, Ebola, Marburg, Zika, others), all caused by viruses, designated as being priority concern potential causes future pandemics. Despite advances in treatments, many lack specific therapeutic options, more importantly, there is a paucity broad-spectrum Additionally, costs current treatments such Remdesivir Paxlovid highlight Cyclic peptides from natural sources or designed through molecular modeling shown promise drugs with stability, low toxicity, target specificity, resistance properties. This review emphasizes urgent develop highlights cyclic sustainable solution combat Further research into these compounds could provide weapon address gaps drug development.

Язык: Английский

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SARS‐CoV‐2 Non-structural protein 1(NSP1) mutation virulence and natural selection: Evolutionary trends in the six continents

Virus Research, Год журнала: 2022, Номер 323, С. 199016 - 199016

Опубликована: Дек. 5, 2022

Rapid transmission and reproduction of RNA viruses prepare conducive conditions to have a high rate mutations in their genetic sequence. The viral make adapt the severe acute respiratory syndrome coronavirus 2 host environment help evolution virus then also caused mortality by that threatens worldwide health. Mutations adaptation escape confrontations are done against it.In present study, we analyzed 6,510,947 sequences non-structural protein 1 as one conserved regions find out frequent substitute amino acids comparison with wild type. NSP1 divided into continents were different.Based on this continental categorization, E87D global vision Europe notably increased. mutation has signed up January 2022 first observed. remarkable mutations, H110Y R24C second third frequencies, respectively.According important role mRNA translation, developing drug design could be so hopeful more effective ways control treatment pandemic disease 2019.

Язык: Английский

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The Effect of Treatment-Associated Mutations on HIV Replication and Transmission Cycles

Viruses, Год журнала: 2022, Номер 15(1), С. 107 - 107

Опубликована: Дек. 30, 2022

HIV/AIDS mortality has been decreasing over the last decade. While promising, this decrease correlated directly with increased use of antiretroviral drugs. As a natural consequence its high mutation rate, treatments provide selection pressure that promotes escape mutants. Individuals may acquire drug-naive strains, or those have already mutated due to treatment. Even within host, affects HIV tropism, where initial infection begins R5-tropic virus, but clinical transition AIDS correlates mutations lead an X4-tropic switch. Furthermore, rate spelled failure for all attempts at effective vaccine. Pre-exposure drugs are currently most drug-based preventatives, their effectiveness is also threatened by viral mutation. From attachment and entry assembly release, steps in replication cycle discussed describe drug mechanisms arise Revealing patterns HIV-1 mutations, effects, coordinated attempt understand control them will current preventative measures treatment options, as well development new ones.

Язык: Английский

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Investigating the effect of ribavirin treatment on genetic mutations in Crimean–Congo haemorrhagic fever virus (CCHFV) through next‐generation sequencing

Journal of Medical Virology, Год журнала: 2023, Номер 95(2)

Опубликована: Фев. 1, 2023

Crimean-Congo haemorrhagic fever (CCHF) is the most widespread tick-borne viral affecting humans, and yet a licensed drug against virus (CCHFV) still not available. While several studies have suggested efficacy of ribavirin CCHFV, current literature remains inconclusive. In this study, we utilised next-generation sequencing to investigate mutagenic effect on CCHFV genome during clinical disease. Samples collected from CCHF patients receiving treatment or supportive care only at Sivas Cumhuriyet University Hospital, Turkey, were analysed. By comparing frequency mutations in each group, found little evidence an overall effect. This suggests that ribavirin, administered acute stages infection (at World Health Organization-recommended dose) unable induce lethal mutagenesis would cause extinction event population reduce viremia.

Язык: Английский

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Prevention and post-exposure management of occupational exposure to Ebola virus

The Lancet Infectious Diseases, Год журнала: 2023, Номер 24(2), С. e93 - e105

Опубликована: Сен. 15, 2023

Язык: Английский

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Ribavirin inhibits the replication of infectious bursal disease virus predominantly through depletion of cellular guanosine pool

Frontiers in Veterinary Science, Год журнала: 2023, Номер 10

Опубликована: Июль 31, 2023

Introduction The antiviral activity of different mutagens against single-stranded RNA viruses is well documented; however, their on the replication double-stranded remains unexplored. This study aims to investigate effect antivirals a chicken embryo fibroblast-adapted Infectious Bursal Disease virus, FVSKG2. further explores mechanism utilized by most effective anti-IBDV agent. Methods cytotoxicity and anti-FVSKG2 agents (ribavirin, 5-fluorouracil, 5-azacytidine, amiloride) were evaluated. virus was serially passaged in fibroblasts 11 times at sub-cytotoxic concentrations ribavirin, 5-fluorouracil or amiloride. Further, possible mutagenic non-mutagenic mechanisms agent explored. Results Discussion Ribavirin least cytotoxic fibroblasts, followed amiloride 5-azacytidine. inhibited FVSKG2 significantly as low 0.05 mM. extinction achieved during serial passage ≥0.05 mM ribavirin; emergence mutagen-resistant not observed until eleventh passage. no mutation 1,898 nucleotides following its five passages presence 0.025 ribavirin. Ribavarin primarily through IMPDH-mediated depletion Guanosine Triphosphate pool cells. However, other like ribavirin-mediated cytokine induction inhibition viral RNA-dependent polymerase interaction with enzyme’s active sites enhance effect. inhibits ds- viruses, likely IMPDH mutagenesis. inhibitory may, be augmented mechanisms, cytokines ribavirin virus.

Язык: Английский

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Shaping the future of antiviral Treatment: Spotlight on Nucleobase-Containing drugs and their revolutionary impact

Bioorganic Chemistry, Год журнала: 2024, Номер 144, С. 107150 - 107150

Опубликована: Янв. 27, 2024

Nucleobases serve as essential molecular frameworks present in both natural and synthetic compounds that exhibit notable antiviral activity. Through modifications, novel nucleobase-containing drugs (NCDs) have been developed, exhibiting enhanced activity against a wide range of viruses, including the recently emerged SARS‑CoV‑2. This article provides detailed examination significant advancements NCDs from 2015 till current, encompassing various aspects concerning their mechanisms action, pharmacology properties. Additionally, discusses prodrugs relevant to scope this review. It fills knowledge gap by examining structure–activity relationship trend therapeutics diverse viral diseases, either approved drugs, clinical candidates or early-stage development prospects. Moreover, highlights on status field study addresses prevailing limitations encountered.

Язык: Английский

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