A Second Opportunity for the Peptide-Based Analogues with γ-Lactam at the P1 Position: Human Cathepsin S Inhibition.

Background/

Objectives

SARS-CoV-2 pandemic led to the identification of peptide-based main protease (Mpro) inhibitors. The overwhelming majority of them carry an electrophilic warhead and a γ-lactam at the P1 position. During the selectivity assessment of an in-house Michael acceptors targeting SARS-CoV-2 Mpro, we unexpectedly observed a significant inhibition of human cathepsin S (hCatS).

Methods

The biological investigation of three compounds (i.e., SPR38, SPR39, and SPR41) against hCatS was performed. The binding mode of SPRs was investigated by docking and molecular dynamics simulations.

Results

Biological investigation has corroborated that hCatS is sensitive to peptide-based analogues harbouring γ-lactam at the P1 position and a vinyl methyl ketone warhead. In silico studies revealed that despite being solvent exposed, the γ-lactam at P1 might be involved in water-mediated H-bonds that could be optimized to gain inhibition potency and selectivity.

Conclusions

The molecules repurposing of peptide-based SARS-CoV-2 Mpro inhibitors carrying the γ-lactam at the P1 site could pave the way for the identification of novel potent and selective hCatS ligands.