Azapeptide Activity-Based Probes for the SARS-CoV-2 Main Protease Enable Visualization of Inhibition in Infected Cells

Roeland Vanhoutte,Marta Barniol-Xicota,Winston Chiu,Laura Vangeel,Dirk Jochmans,Steven De Jonghe, Hadeer Zidane,Haim M. Barr,Nir London,Johan Neyts,Steven H. L. Verhelst

Chemical Science（2023）SCI 1区SCI 2区

Katholieke Univ Leuven | Weizmann Inst Sci

Cited 3|Views42

Abstract

The COVID-19 pandemic has revealed the vulnerability of the modern, global society. With expected waves of future infections by SARS-CoV-2, treatment options for infected individuals will be crucial in order to decrease mortality and hospitalizations. The SARS-CoV-2 main protease is a validated drug target, for which the first inhibitor has been approved for use in patients. To facilitate future work on this drug target, we designed a solid-phase synthesis route towards azapeptide activity-based probes that are capped with a cysteine-reactive electrophile for covalent modification of the active site of Mpro. This design led to the most potent ABP for Mpro and one of the most potent inhibitors reported thus far. We demonstrate that this ABP can be used to visualize Mpro activity and target engagement by drugs in infected cells.

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