2. Academic Validation
  3. Potent antiviral activity of simnotrelvir against key epidemic SARS-CoV-2 variants with a high resistance barrier

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

  • Antimicrob Agents Chemother. 2025 Mar 10:e0155624. doi: 10.1128/aac.01556-24.
Liwei Zhao # 1,  Chuang Li # 1,  Mengyu Wang # 2 3,  Minyun Zhou 2 3,  Lei Jiang 4 5,  Wanying Zhang 6,  Jie Yu 7,  Wei Wang 2,  Kangping Zhou 8,  Kai Pan 8,  Hoi-Yan Lam 9,  Ivan Fan-Ngai Hung 9 10,  Kwok-Hung Chan 9 11,  Lian Liu 2 3,  Feng Wang 2 3,  Xiaofeng Zhao 2 3,  Yuxin Chen 1 7
Affiliations

Affiliations

  • 1 Department of Laboratory Medicine, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China.
  • 2 Jiangsu Simcere Pharmaceutical Company Limited, Nanjing, Jiangsu, China.
  • 3 State Key Laboratory of Neurology and Oncology Drug Development, Nanjing, China.
  • 4 Simcere Zaiming Pharmaceutical Company Limited, Shanghai, China.
  • 5 Department of Chemical Engineering, Tsinghua University, Beijing, China.
  • 6 Department of Laboratory Medicine, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, Jiangsu, China.
  • 7 Department of Laboratory Medicine, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, Jiangsu, China.
  • 8 Hubei Provincial Center for Disease Control and Prevention, Wuhan, Hubei, China.
  • 9 Department of Microbiology, State Key Laboratory of Emerging Infectious Diseases, Carol Yu Centre for Infection,The University of Hong Kong, Hong Kong SAR, China.
  • 10 Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong SAR, China.
  • 11 Centre for Virology, Vaccinology and Therapeutics, Hong Kong Science and Technology Park, Hong Kong SAR, China.
  • # Contributed equally.
PMID: 40062859 DOI: 10.1128/aac.01556-24
Abstract

Simnotrelvir is an oral small-molecule Antiviral agent targeting the 3C-like protease (3CLpro) 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 3CLpro 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 IC50 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 3CLpro 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

3C-like protease; SARS-CoV-2; antiviral efficacy; antiviral resistance; simnotrelvir.

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