Nanomolar anti-SARS-CoV-2 Omicron activity of the host-directed TMPRSS2 inhibitor N-0385 and synergistic action with direct-acting antivirals

Antiviral Research, Год журнала: 2024, Номер 225, С. 105869 - 105869

Опубликована: Март 26, 2024

SARS-CoV-2 Omicron subvariants with increased transmissibility and immune evasion are spreading globally alarming persistence. Whether the mutations evolution of spike (S) alter viral hijacking human TMPRSS2 for entry remains to be elucidated. This is particularly important investigate because large number diversity S reported since emergence BA.1. Here we report that a molecular determinant all clinical isolates tested in lung cells, including ancestral (BA.1, BA.2, BA.5), contemporary (BQ.1.1, XBB.1.5, EG.5.1) currently circulating BA.2.86. First, used co-transfection assay demonstrate endoproteolytic cleavage by subvariants. Second, found N-0385, highly potent inhibitor, robust inhibitor virus-like particles harbouring protein Third, show N-0385 exhibits nanomolar broad-spectrum antiviral activity against live Calu-3 cells primary patient-derived bronchial epithelial cells. Interestingly, 10-20 times more than repositioned camostat, BA.5, EG.5.1, We further shows broad synergistic clinically approved direct-acting antivirals (DAAs), i.e., remdesivir nirmatrelvir, subvariants, demonstrating potential therapeutic benefits multi-targeted treatment based on DAAs.

Язык: Английский

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Computational Approaches in the Discovery and Development of Therapeutic and Prophylactic Agents for Viral Diseases

Current Topics in Medicinal Chemistry, Год журнала: 2022, Номер 22(26), С. 2190 - 2206

Опубликована: Окт. 1, 2022

Abstract: Over the last two decades computational technologies have always played a crucial role in anti-viral drug development. Whenever virus spreads and becomes threat to global health it brings along challenge develop new therapeutics prophylactics. Computational vaccine discovery evolved at breakneck pace over years. Some interesting examples of are anti-AIDS drugs, where HIV protease reverse transcriptase been targeted by agents developed using methods. Various methods that applied research include, ligand-based rely on known active compounds i.e., pharmacophore modeling, machine learning or classical QSAR; structure-based an experimentally determined 3D structure targets molecular docking dynamics for development vaccines such as vaccinology; structural vaccinology epitope prediction. In this review we summarize these approaches they were battle viral diseases underscore their importance research. We discuss small molecules against, human immunodeficiency virus, yellow fever, papilloma SARS-CoV-2, other viruses. tools available abovementioned purposes listed described. A discussion application artificial intelligence-based antiviral has also included.

Язык: Английский

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Seven classes of antiviral agents

Cellular and Molecular Life Sciences, Год журнала: 2022, Номер 79(12)

Опубликована: Ноя. 27, 2022

The viral epidemics and pandemics have stimulated the development of known discovery novel antiviral agents. About a hundred mono- combination drugs been already approved, whereas thousands are in development. Here, we briefly reviewed 7 classes agents: neutralizing antibodies, recombinant soluble human receptors, CRISPR/Cas systems, interferons, peptides, nucleic acid polymers, small molecules. Interferons some molecules alone or combinations possess broad-spectrum activity, which could be beneficial for treatment emerging re-emerging infections.

Язык: Английский

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Repurposing of the antibiotic nitroxoline for the treatment of mpox

Journal of Medical Virology, Год журнала: 2023, Номер 95(3)

Опубликована: Март 1, 2023

Abstract The antiviral drugs tecovirimat, brincidofovir, and cidofovir are considered for mpox (monkeypox) treatment despite a lack of clinical evidence. Moreover, their use is affected by toxic side‐effects (brincidofovir, cidofovir), limited availability (tecovirimat), potentially resistance formation. Hence, additional, readily available needed. Here, therapeutic concentrations nitroxoline, hydroxyquinoline antibiotic with favourable safety profile in humans, inhibited the replication 12 virus isolates from current outbreak primary cultures human keratinocytes fibroblasts skin explant model interference host cell signalling. Tecovirimat, but not resulted rapid development. Nitroxoline remained effective against tecovirimat‐resistant strain increased anti‐mpox activity tecovirimat brincidofovir. nitroxoline bacterial viral pathogens that often co‐transmitted mpox. In conclusion, repurposing candidate due to both antimicrobial activity.

Язык: Английский

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The RNA Interference Effector Protein Argonaute 2 Functions as a Restriction Factor Against SARS-CoV-2

Journal of Molecular Biology, Год журнала: 2023, Номер 435(16), С. 168170 - 168170

Опубликована: Июнь 3, 2023

Язык: Английский

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