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.
Smith et al. (2026) studied this question.