Favipiravir Analogues as Inhibitors of SARS-CoV-2 RNA-Dependent RNA Polymerase, Combined Quantum Chemical Modeling, Quantitative Structure–Property Relationship, and Molecular Docking Study

Molecules, Journal Year: 2024, Volume and Issue: 29(2), P. 441 - 441

Published: Jan. 16, 2024

Our study was motivated by the urgent need to develop or improve antivirals for effective therapy targeting RNA viruses. We hypothesized that analogues of favipiravir (FVP), an inhibitor RNA-dependent polymerase (RdRp), could provide more nucleic acid recognition and binding processes while reducing side effects such as cardiotoxicity, hepatotoxicity, teratogenicity, embryotoxicity. proposed a set FVP together with their forms triphosphate new SARS-CoV-2 RdRp inhibitors. The main aim our investigate changes in mechanism capacity resulting from these modifications. Using three different approaches, QTAIM, QSPR, MD, differences reactivity, toxicity, efficiency, ability be incorporated were assessed. Two quantum chemical reactivity descriptors, relative electro-donating electro-accepting power, defined successfully applied. Moreover, quantitative method comparing modes developed based on mathematical metrics atypical radar plot. These methods deep insight into desirable properties responsible inhibiting RdRp, allowing ligands conveniently screened. modification structure seems its enhance productive mode binding. In particular, two (the trifluoro- cyano-) bind very strongly template, primer, cofactors, thus may constitute good alternative FVP.

Language: Английский

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Comparison of azvudine, molnupiravir, and nirmatrelvir/ritonavir in adult patients with mild-to-moderate COVID-19: a retrospective cohort study

Scientific Reports, Journal Year: 2024, Volume and Issue: 14(1)

Published: Feb. 9, 2024

Abstract This study aimed to explore the effectiveness and safety of azvudine, nirmatrelvir/ritonavir, molnupiravir in adult patients with mild-to-moderate COVID-19. retrospective cohort included COVID-19 (asymptomatic, mild, common types) at First Hospital Changsha (Hunan Province, China) between March November 2022. Eligible were classified into or groups according antiviral agents they received. The outcomes times nucleic acid negative conversion (NANC). 157 treated azvudine (n = 66), nirmatrelvir/ritonavir 25). There no statistically significant differences time from diagnosis NANC among molnupiravir, [median, 9 (95% CI 9–11) vs. 11 10–12) 8–12) days, P 0.15], administration 8–10) 10 9.48–11) 8.708 7.51–11) 0.50], hospital stay 11–13) 13 12–14) 12 10–14) 0.14], even after adjustment for sex, age, type, comorbidities, Ct level, treatment, number symptoms. cumulative rates 15.2%/12.3%/16.0% day 5 ( 0.858), 34.8%/21.5%/32.0% 7 0.226), 66.7%/52.3%/60.0% days 0.246), 86.4%/86.2%/80.0% 14 0.721). No serious adverse events reported. Azvudine may be comparable regarding NANC, stay, AEs.

Language: Английский

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Evaluation of selected inflammatory markers in cats with feline infectious peritonitis before and after therapy

BMC Veterinary Research, Journal Year: 2025, Volume and Issue: 21(1)

Published: May 9, 2025

Feline infectious peritonitis (FIP), once considered fatal disease with a mortality rate approaching 100%, has experienced new therapeutic breakthrough in recent years. The aim of our study was to evaluate selected clinicopathological parameters before and after GS- 445124-based treatment FIP cats, which could serve as potential candidates for predicting success monitoring progress. Pre-treatment haematological 32 treated cats showed moderate leukocytosis, neutrophilia, lymphopenia anaemia, normalised post-treatment. values haemogram-derived inflammatory markers (ratio neutrophils lymphocytes, platelets lymphocytes monocytes the systemic immune-inflammatory index) differed significantly from those healthy between patients effusive non-effusive (p < 0.05). Post-treatment, only ratio remained higher; other three were comparable control group. biochemical results characteristic abnormalities (e.g. hyperproteinaemia, hypoalbuminemia, hypergammaglobulinemia, hyperbilirubinemia), treatment. Lactate dehydrogenase activities did not differ treatment, except relapse one non-responder, had markedly elevated at time diagnosis. Analysis archived blood samples using ELISA revealed significant differences concentration acute-phase protein haptoglobin = 0.004) pro-inflammatory cytokine tumour necrosis factor-α 0.028) therapy. Therapy didn't elicit any statistically changes concentrations ferritin, interleukin- 1β 6. Our findings demonstrate that successful leads highly most parameters, including markers. latter offer simple, inexpensive readily available alternative more commonly used acute phase proteins Successful therapy decrease an increase factor-α. In study, unfavourable outcome marked lactate activity therapy, suggesting this parameter be promising prognostic factor larger studies.

Language: Английский

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In vitro testing of host-targeting small molecule antiviral matriptase/TMPRSS2 inhibitors in 2D and 3D cell-based assays

Biomedicine & Pharmacotherapy, Journal Year: 2023, Volume and Issue: 168, P. 115761 - 115761

Published: Oct. 20, 2023

The outbreak of coronavirus disease 2019 (COVID-19) pandemic strongly stimulated the development small molecule antivirals selectively targeting type II transmembrane serine proteases (TTSP), required for host-cell entry numerous viruses. A set 3-amidinophenylalanine derivatives (MI-21, MI-472, MI-477, MI-485, MI-1903 and MI-1904), which inhibit cleavage certain viral glycoproteins was characterized in 2D 3D primary human hepatocyte models on collagen- Matrigel-coating using a CCK-8 assay to evaluate their cytotoxicity, resorufin-based method detect redox imbalances, fluorescence ultrafiltration experiments interactions with serum albumin (HSA) α-acidic glycoprotein (AGP), luminescence measurement assess CYP3A4 modulation. For elucidation selectivity applied compounds towards matriptase, protease 2 (TMPRRS2), thrombin factor Xa (FXa) Ki values were determined. It proven that cell viability only deteriorated by inhibitor MI-1903, status not influenced administration selected inhibitors at 50 µM 24 h. MI-472 MI-477 formed relatively stable complexes AGP. inhibition found be strong PHHs exposed all exception MI-21, seems promising drug candidate also due its better matriptase TMPRSS2 over blood clotting FXa. Our vitro pharmacokinetic screening these helps select best safety profile suitable further preclinical characterization without animal sacrifice.

Language: Английский

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Molecular Factors and Pathways of Hepatotoxicity Associated with HIV/SARS-CoV-2 Protease Inhibitors

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(9), P. 7938 - 7938

Published: April 27, 2023

Antiviral protease inhibitors are peptidomimetic molecules that block the active catalytic center of viral proteases and, thereby, prevent cleavage polyprotein precursors into maturation. They continue to be a key class antiviral drugs can used either as boosters for other classes antivirals or major components current regimens in therapies treatment infections with human immunodeficiency virus (HIV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, sustained/lifelong combined substance(s) often leads hepatic side effects such lipid abnormalities, insulin resistance, hepatotoxicity. The underlying pathogenic mechanisms not fully known under continuous investigation. This review focuses on general well specific molecular inhibitor-induced hepatotoxicity involving transporter proteins, apolipoprotein B, cytochrome P450 isozymes, insulin-receptor substrate 1, Akt/PKB signaling, lipogenic factors, UDP-glucuronosyltransferase, pregnane X receptor, hepatocyte nuclear factor 4α, reactive oxygen species, inflammatory cytokines, off-target proteases, small GTPase Rab proteins related ER-Golgi trafficking, organelle stress, liver injury. Potential pharmaceutical/therapeutic solutions drug-induced also discussed.

Language: Английский

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COVID-19 and suspected drug-induced liver injury

Elsevier eBooks, Journal Year: 2024, Volume and Issue: unknown, P. 267 - 285

Published: Jan. 1, 2024

Language: Английский

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Development and Validation of In-vitro Release Study of Molnupiravir Capsules by RP-HPLC

Current Pharmaceutical Analysis, Journal Year: 2023, Volume and Issue: 19(7), P. 577 - 585

Published: Aug. 22, 2023

Introduction: The coronavirus disease-2019 (COVID-19) outbreak all over the world has led researchers to strive develop treatment and preventive measures control its progression. Methods: Molnupiravir, a prodrug of synthetic nucleoside derivative N-4-hydroxycytidine was found be promising candidate against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Results: It could significantly reduce risk hospitalization mortality among patients with positive SARS-CoV-2 reports. In this study, an RP-HPLC method UV detection developed determine dissolution release in capsule dosage form. validated as per International Council for Harmonization (ICH) guidelines. Conclusion: evaluated applicability using various parameters. simple, rapid, selective, sensitive, accurate, precise, robust rugged method.

Language: Английский

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