2. Academic Validation
  3. Pharmacokinetics, pathology and efficacy of SARS-CoV-2 main protease inhibitor VPC285785 in a murine model of coronavirus infection

Pharmacokinetics, pathology and efficacy of SARS-CoV-2 main protease inhibitor VPC285785 in a murine model of coronavirus infection

  • Sci Rep. 2026 Feb 2;16(1):6905. doi: 10.1038/s41598-026-36842-2.
Jason R Smith 1 2,  Ayelen Toro 3 4,  Agustina Sabater 3 4 5 6,  Suzana Kovacic 7,  Fuqiang Ban 8,  Ana P Arevalo 9,  Martina Crispo 9,  Geraldine Gueron 3 4,  Robert N Young 7,  Artem Cherkasov 10
Affiliations

Affiliations

  • 1 Department of Urologic Science, Vancouver Prostate Centre, University of British Columbia, 2660 Oak Street, Vancouver, B.C., V6H3Z6, Canada. jsmith@prostatecentre.com.
  • 2 Department of Chemistry, Simon Fraser University, Burnaby, B.C., V5A1S6, Canada. jsmith@prostatecentre.com.
  • 3 Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires C1428EGA, Argentina.
  • 4 Instituto de Química Biológica de La Facultad de Ciencias Exactas y Naturales (IQUIBICEN), CONICET-Universidad de Buenos Aires, C1428EGA, Buenos Aires, Argentina.
  • 5 Instituto de Tecnología (INTEC), Universidad Argentina de La Empresa (UADE), C1073AAO, Buenos Aires, Argentina.
  • 6 Department of Genitourinary Medical Oncology and The David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
  • 7 Department of Chemistry, Simon Fraser University, Burnaby, B.C., V5A1S6, Canada.
  • 8 Department of Urologic Science, Vancouver Prostate Centre, University of British Columbia, 2660 Oak Street, Vancouver, B.C., V6H3Z6, Canada.
  • 9 Laboratory Animal Biotechnology Unit (UBAL), Mataojo 2020, Institut Pasteur de Montevideo, 11400, Montevideo, Uruguay.
  • 10 Department of Urologic Science, Vancouver Prostate Centre, University of British Columbia, 2660 Oak Street, Vancouver, B.C., V6H3Z6, Canada. acherkasov@prostatecentre.com.
PMID: 41629446 DOI: 10.1038/s41598-026-36842-2
Abstract

Herein we report the development of novel covalent inhibitors of the SARS-CoV-2 main protease (Mpro). The developed compounds VPC285785 and VPC285786 demonstrated moderate inhibition of Mpro (IC50 0.8 µM vs. Nirmatrelvir 0.03 µM), whereas VPC285786 additionally inhibited human Cathepsin L (CatL; IC50 4.2 µM vs Nirmatrelvir > 100 µM). In vitro metabolic stability studies in human and mouse microsomes revealed that VPC285786 demonstrated enhanced metabolic stability compared to Nirmatrelvir, with minimal turnover observed during the experimental window. Subsequent mass spectrometry analysis identified putative metabolic products consistent with previously reported oxidation patterns. Pharmacokinetic studies in mice demonstrated that VPC285785 achieved 15% oral bioavailability, supporting the potential for oral administration, whereas VPC285786 showed limited oral exposure despite superior metabolic stability. A side-by-side efficacy study of VPC285785 and Nirmatrelvir in a Murine Hepatitis Virus (MHV) Infection model demonstrated that VPC285785 significantly reduced viral load in liver, brain, and spleen tissues compared to vehicle- and Nirmatrelvir-treated controls, while maintaining healthy liver function parameters. These results lay the foundation for further development of VPC285785-series antivirals that could be used as oral, single-agent therapies for SARS-CoV-2 Infection, particularly given their dual-targeting mechanism and favorable toxicity profile.

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