# Structure-Based Design of Covalent SARS-CoV‑2 Main Protease Inhibitors Targeting the Nirmatrelvir-Resistant E166 Mutants

## TL;DR

Researchers designed a new drug, Jun13698, that effectively inhibits a SARS-CoV-2 protease mutant resistant to the current treatment nirmatrelvir.

## Contribution

The study introduces Jun13698, a novel covalent inhibitor targeting nirmatrelvir-resistant E166 mutants of the SARS-CoV-2 main protease.

## Key findings

- Jun13698 shows potent inhibition of both wild-type and E166V/A mutant SARS-CoV-2 main protease.
- Structural and molecular dynamics studies confirm Jun13698's stable binding to resistant protease variants.
- The compound demonstrates strong antiviral activity, suggesting potential as a next-generation treatment.

## Abstract

The COVID-19 pandemic spurred the rapid development of
nirmatrelvir,
a main protease (Mpro) inhibitor now widely prescribed
as part of Paxlovid (nirmatrelvir plus ritonavir). However, increasing
use has raised concerns about drug resistance. Resistance selection
studies have identified multiple Mpro mutations, with E166V
emerging as a particularly resistant variant. Sequencing data from
COVID-19 patients confirms E166V as a clinically relevant mutation,
and importantly, this substitution also confers cross-resistance to
several next-generation Mpro inhibitors under development.
In response, this study reports the rational design of inhibitors
active against nirmatrelvir-resistant E166V/A mutants. The lead candidate, Jun13698, shows potent inhibition of both wild-type Mpro and the E166V/A mutants. Structural studies and molecular
dynamics simulations reveal that Jun13698 forms stable
complexes with wild-type and mutant proteases, consistent with its
potent enzymatic and antiviral activity. Together, these findings
position Jun13698 as a promising next-generation Mpro inhibitor capable of overcoming clinically relevant nirmatrelvir
resistance.