Development of peptide-based SARS CoV-2 Mpro/hCatL dual inhibitors as antiviral agents

SARS-CoV-2 is the virus responsible for COVID-19. Despite the significant efforts of the scientific community, the long-term efficacy of antibodies and the emergence of new variants remain uncertain for the coming years. In light of this, the development of effective antiviral agents continues to be a priority in the fight against COVID-19. Main protease (Mpro) is a crucial cysteine protease of SARSCoV- 2 involved in the cleavage of polyproteins into non-structural proteins.1 In addition to the viral components, human cathepsin L (hCatL) plays a key role in facilitating the virus entry into host cells.2 Starting from hit-compound 1,3 a series of peptide-based Michael acceptors as potential dual Mpro/hCatL inhibitors was developed (Figure 1). The new molecules contain a methyl vinyl ketone warhead, a cyclic pentatomic glutamine surrogate at the P1 site, a panel of aliphatic amino acids at the P2 site, and a monofluoro-substituted benzoyl group as the N-terminal cap. Seven Mpro/hCatL dual inhibitors with Ki values in the micromolar and nanomolar range against the viral and human targets, respectively, were identified. Three of them showed promising EC50 values in the low micromolar range against Huh-7-ACE2 infected cells without cytotoxicity. Selectivity for the targets was assessed. Docking studies were conducted to gain comprehensive insight into the structureactivity relationship.