Potent antiviral activity of simnotrelvir against key epidemic SARS-CoV-2 variants with a high resistance barrier DOI Creative Commons

Liwei Zhao,

Chuang Li,

Mengyu Wang

et al.

Antimicrobial Agents and Chemotherapy, Journal Year: 2025, Volume and Issue: unknown

Published: March 10, 2025

ABSTRACT Simnotrelvir is an oral small-molecule antiviral agent targeting the 3C-like protease (3CL pro ) of SARS-CoV-2, proven effective against Delta variant with favorable pharmacokinetics and safety in preclinical study. In this study, we further evaluated efficacy simnotrelvir a range emerging Omicron variants, including BA.1, BA.4, BA.5, CH.1.1, XBB.1.5, XBB.1.16, EG.5, JN.1. vitro assays Vero E6 cells confirmed that exhibited robust activity across these comparable to Food Drug Administration (FDA)-approved drug nirmatrelvir. Additionally, demonstrated inhibition several nirmatrelvir-resistant SARS-CoV-2 3CL mutants, A260V, Y54A, (T21I + S144A), F140A, H172Y, E166V. Importantly, showed better potency E166V mutation compared Resistance selection studies revealed BA.5 developed reduced sensitivity after 5 10 passages, increasing IC 50 values by 3.2 4.5-fold, respectively, while HCoV-OC43 8.3-fold increase 12 passages. Despite this, simnotrelvir’s overall remains strong. Furthermore, clinical trials combining ritonavir significantly shortened symptom resolution COVID-19 patients. Genomic analysis treated patients found random nucleotide substitutions but no significant mutations linked resistance. conclusion, shows strong variants maintains high barrier resistance, reinforcing its potential as therapeutic option for current future variants.

Language: Английский

Dynamic Cap‐Mediated Substrate Access and Potent Inhibitor Design of Monkeypox Virus I7L Protease DOI Creative Commons

Haixia Su,

Guoqing Wu,

Muya Xiong

et al.

Advanced Science, Journal Year: 2025, Volume and Issue: unknown

Published: April 7, 2025

Abstract Monkeypox virus (MPXV), an orthopoxvirus that has long been endemic in Africa, posed a significant global health threat since 2022. The I7L protease, highly conserved cysteine proteinase essential for replication, represents promising target broad‐spectrum antiviral drug development. Here, the first crystal structure of MPXV protease is reported, revealing its unique dimeric form and different conformations cap region nearby active site. Molecular dynamics simulations AlphaFold3 prediction protease‐substrate structures both suggest this flexible acts as conformational switch, regulating substrate access to Additionally, structural basis recognition catalytic mechanism are elucidated, mapping determinants specificity. These insights enable us design covalent inhibitors mimic natural substrates develop fluorescence resonance energy transfer (FRET)‐based assay effectively assess inhibitory activity, leading discovery first‐in‐class with nanomolar potency. Therefore, work provides comprehensive understanding protease's structure, dynamics, function, presents example successful rational peptidomimetic inhibitors, serving good starting point development against MPXV.

Language: Английский

Citations

0
Potent antiviral activity of simnotrelvir against key epidemic SARS-CoV-2 variants with a high resistance barrier DOI Creative Commons

Liwei Zhao,

Chuang Li,

Mengyu Wang

et al.

Antimicrobial Agents and Chemotherapy, Journal Year: 2025, Volume and Issue: unknown

Published: March 10, 2025

ABSTRACT Simnotrelvir is an oral small-molecule antiviral agent targeting the 3C-like protease (3CL pro ) of SARS-CoV-2, proven effective against Delta variant with favorable pharmacokinetics and safety in preclinical study. In this study, we further evaluated efficacy simnotrelvir a range emerging Omicron variants, including BA.1, BA.4, BA.5, CH.1.1, XBB.1.5, XBB.1.16, EG.5, JN.1. vitro assays Vero E6 cells confirmed that exhibited robust activity across these comparable to Food Drug Administration (FDA)-approved drug nirmatrelvir. Additionally, demonstrated inhibition several nirmatrelvir-resistant SARS-CoV-2 3CL mutants, A260V, Y54A, (T21I + S144A), F140A, H172Y, E166V. Importantly, showed better potency E166V mutation compared Resistance selection studies revealed BA.5 developed reduced sensitivity after 5 10 passages, increasing IC 50 values by 3.2 4.5-fold, respectively, while HCoV-OC43 8.3-fold increase 12 passages. Despite this, simnotrelvir’s overall remains strong. Furthermore, clinical trials combining ritonavir significantly shortened symptom resolution COVID-19 patients. Genomic analysis treated patients found random nucleotide substitutions but no significant mutations linked resistance. conclusion, shows strong variants maintains high barrier resistance, reinforcing its potential as therapeutic option for current future variants.

Language: Английский

Citations

0