Potent antiviral activity of simnotrelvir against key epidemic SARS-CoV-2 variants with a high resistance barrier
Liwei Zhao, Chuang Li, Mengyu Wang, Minyun Zhou, Lei Jiang, Wanying Zhang, Jie Yu, Wei Wang, Kangping Zhou, Kai Pan, Hoi-Yan Lam, Ivan Fan-Ngai Hung, Kwok-Hung Chan, Lian Liu, Feng Wang, Xiaofeng Zhao, Yuxin Chen
Antimicrobial Agents and Chemotherapy, doi:10.1128/aac.01556-24
Simnotrelvir is an oral small-molecule antiviral agent targeting the 3C-like protease (3CL pro ) of SARS-CoV-2, proven effective against the Delta variant with favorable pharmacokinetics and safety in preclinical study. In this study, we further evaluated the antiviral efficacy of simnotrelvir against a range of emerging Omicron variants, including BA.1, BA.4, BA.5, CH.1.1, XBB.1.5, XBB.1.16, EG.5, and JN.1. In vitro assays with Vero E6 cells confirmed that simnotrelvir exhibited robust antiviral activity across these variants, comparable to the Food and Drug Administration (FDA)-approved drug nirmatrelvir. Additionally, simnotrelvir demonstrated effective inhibition against several nirmatrelvir-resistant SARS-CoV-2 3CL pro mutants, including A260V, Y54A, (T21I + S144A), F140A, H172Y, and E166V. Importantly, simnotrelvir showed better potency against the E166V mutation compared to nirmatrelvir. Resistance selection studies revealed that BA.5 developed reduced sensitivity after 5 and 10 passages, increasing the IC 50 values by 3.2 and 4.5-fold, respectively, while HCoV-OC43 showed an 8.3-fold increase after 12 passages. Despite this, simnotrelvir's overall efficacy remains strong. Furthermore, clinical trials demonstrated that combining simnotrelvir with ritonavir significantly shortened symptom resolution in COVID-19 patients. Genomic analysis of treated patients found random nucleotide substitutions but no significant mutations linked to 3CL pro resistance. In conclusion, simnotrelvir shows strong antiviral activity against SARS-CoV-2 variants and maintains a high barrier to resistance, reinforcing its potential as an effective therapeutic option for current and future SARS-CoV-2 variants. KEYWORDS simnotrelvir, 3C-like protease, SARS-CoV-2, antiviral efficacy, antiviral resistance T he severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged at the end of 2019, causing severe acute respiratory coronavirus disease 2019 (COVID-19) and triggering a global pandemic (1, 2). Large-scale vaccination is considered crucial for controlling the COVID-19 pandemic. However, the emergence of new SARS-CoV-2 variants, such as KP.2 and KP.3, is rapidly increasing infection rates globally, becoming dominant strains in circulation (3). According to World Health Organization (WHO) surveillance data, as of 12 August 2024, the global infection rate has reached 21% (4). It is possibly due to the remarkable mutations of the Omicron variant and the waned immunity elicited by either infection or vaccination (3, 4). COVID-19 therapeu tics, especially monoclonal antibodies, had lost their efficacy against newly emerging SARS-CoV-2 variants, highlighting the need for more effective antiviral drugs to treat COVID-19. The coronavirus 3C-like protease (3CL pro ), also known as main protease (M pro ), highly conserved across a range of pathogenic coronaviruses, is responsible for the cleavage of two polyproteins (pp1a and pp1b) during viral replication (5-7),..
AUTHOR AFFILIATIONS
ETHICS APPROVAL This research protocol was approved by the Clinical Trial Ethics Committee of China-Japan Friendship Hospital Drug (YW2022-035-09) and was carried out in accordance with The Code of Ethics of the World Medical Association (Declaration of Helsinki).
ADDITIONAL FILES The following material is available online.
Supplemental Material Supplemental tables (AAC01556-24-S0001.docx). Tables S1 and S2 .
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"abstract": "<jats:title>ABSTRACT</jats:title>\n <jats:sec>\n <jats:title/>\n <jats:p>\n Simnotrelvir is an oral small-molecule antiviral agent targeting the 3C-like protease (3CL\n <jats:sup>pro</jats:sup>\n ) of SARS-CoV-2, proven effective against the Delta variant with favorable pharmacokinetics and safety in preclinical study. In this study, we further evaluated the antiviral efficacy of simnotrelvir against a range of emerging Omicron variants, including BA.1, BA.4, BA.5, CH.1.1, XBB.1.5, XBB.1.16, EG.5, and JN.1.\n <jats:italic>In vitro</jats:italic>\n assays with Vero E6 cells confirmed that simnotrelvir exhibited robust antiviral activity across these variants, comparable to the Food and Drug Administration (FDA)-approved drug nirmatrelvir. Additionally, simnotrelvir demonstrated effective inhibition against several nirmatrelvir-resistant SARS-CoV-2 3CL\n <jats:sup>pro</jats:sup>\n mutants, including A260V, Y54A, (T21I + S144A), F140A, H172Y, and E166V. Importantly, simnotrelvir showed better potency against the E166V mutation compared to nirmatrelvir. Resistance selection studies revealed that BA.5 developed reduced sensitivity after 5 and 10 passages, increasing the IC\n <jats:sub>50</jats:sub>\n values by 3.2 and 4.5-fold, respectively, while HCoV-OC43 showed an 8.3-fold increase after 12 passages. Despite this, simnotrelvir’s overall efficacy remains strong. Furthermore, clinical trials demonstrated that combining simnotrelvir with ritonavir significantly shortened symptom resolution in COVID-19 patients. Genomic analysis of treated patients found random nucleotide substitutions but no significant mutations linked to 3CL\n <jats:sup>pro</jats:sup>\n resistance. In conclusion, simnotrelvir shows strong antiviral activity against SARS-CoV-2 variants and maintains a high barrier to resistance, reinforcing its potential as an effective therapeutic option for current and future SARS-CoV-2 variants.\n </jats:p>\n </jats:sec>",
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