This report discusses preliminary result of a study into a series of new poly-N-substituted glycines (peptoids) with nitrile warheads as chymotrypsin-like cysteine protease (3CL Pro) inhibitors to target severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19. Pfizer’s Paxlovid (PF-07321332; ritonavir) has demonstrated efficacy as a potent SARS-CoV-2 3CL protease inhibitor and has received conditional authorization for use as an orally administered treatment against SAR-COV-2. However, due to its susceptibility to cytochrome P450 (CYP) 3A activity and low bioavailability, PF-07321332 (nirmatrelvir) is co-administrated with a low dose of ritonavir, a well-known cytochrome P450 (CYP) 3A inhibitor. To reduce these limitations, this study utilizes peptoids (poly-N-substituted glycines), equipped with nitrile warheads, as peptide mimetics since peptoids are relatively more resistant to protease degradation in general. The result shows that some synthetic peptoids involved in the study exhibited inhibitory activity against SARS-CoV-2 3CLPro. Future direction includes modification of leads, screening for improved bioactivity, and xenobiotic metabolic studies. All synthetic peptoids were characterized by ESI-MS, 1H and 13C NMR spectroscopy.

Poly-N-substituted glycines equipped with nitrile warheads as SARS-CoV-2 3CLpro inhibitors

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