# Insights into the complexity of SARS-CoV-2 Mpro inhibition: Ebselen and its derivatives impair dimerisation of the enzyme

## TL;DR

This study explores how Ebselen and its derivatives inhibit the SARS-CoV-2 protease by altering its structure, potentially offering a new treatment for COVID-19.

## Contribution

The study reveals that Ebselen and its derivatives inhibit SARS-CoV-2 Mpro by inducing a dimer-to-monomer shift, a novel mechanism of action.

## Key findings

- Ebselen and its derivatives bind covalently to SARS-CoV-2 Mpro with multiple stoichiometry.
- The compounds induce a dose-dependent shift in the dimer-monomer equilibrium of the enzyme.
- The monomeric state of the protease is likely inactive, contributing to the observed inhibition.

## Abstract

The SARS-CoV-2 Main Protease (Mpro), a key enzyme for viral replication, represents a highly attractive target for the development of broad-spectrum anti-coronavirus therapeutics. The organoselenium drug Ebselen has shown potent in vitro inhibition of Mpro as well as antiviral activity, granting clinical interest as a COVID-19 treatment option. Here we show that Ebselen and selected derivatives with human neutrophil elastase (HNE) inhibition and anti-radical activity are able to bind covalently to the viral enzyme with multiple stoichiometry, exhibiting inhibitory activity towards SARS-CoV-2 Mpro with potencies in the nanomolar range. Employing a mass spectrometry-based approach, we show that, upon binding to the target, Ebselen and its derivatives induce a dose-dependent shift in the dimer-monomer equilibrium, favouring the inactive monomeric state of the viral protease and possibly contributing to the observed in vitro inhibition.