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

## TL;DR

Researchers found that some SARS-CoV-2 inhibitors also block human cathepsin S, suggesting new drug possibilities.

## Contribution

Discovery that γ-lactam-based SARS-CoV-2 inhibitors can inhibit human cathepsin S, offering a new drug design strategy.

## Key findings

- Peptide-based analogues with γ-lactam at P1 inhibit human cathepsin S.
- Molecular simulations suggest γ-lactam can form water-mediated hydrogen bonds to enhance inhibition.
- Repurposing these inhibitors could lead to potent and selective hCatS ligands.

## Abstract

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.