SARS-CoV-2 Mpro inhibitors and activity-based probes for patient-sample imaging

Wioletta Rut*, Katarzyna Groborz, Linlin Zhang, Xinyuanyuan Sun, Mikolaj Zmudzinski, Bartlomiej Pawlik, Xinyu Wang, Dirk Jochmans, Johan Neyts, Wojciech Młynarski, Rolf Hilgenfeld, Marcin Drag

*Corresponding author for this work

Abstract

In December 2019, the first cases of infection with a novel coronavirus, SARS-CoV-2, were diagnosed. Currently, there is no effective antiviral treatment for COVID-19. To address this emerging problem, we focused on the SARS-CoV-2 main protease that constitutes one of the most attractive antiviral drug targets. We have synthesized a combinatorial library of fluorogenic substrates with glutamine in the P1 position. We used it to determine the substrate preferences of the SARS-CoV and SARS-CoV-2 main proteases. On the basis of these findings, we designed and synthesized a potent SARS-CoV-2 inhibitor (Ac-Abu-dTyr-Leu-Gln-VS, half-maximal effective concentration of 3.7 µM) and two activity-based probes, for one of which we determined the crystal structure of its complex with the SARS-CoV-2 Mpro. We visualized active SARS-CoV-2 Mpro in nasopharyngeal epithelial cells of patients suffering from COVID-19 infection. The results of our work provide a structural framework for the design of inhibitors as antiviral agents and/or diagnostic tests. [Figure not available: see fulltext.].

Original languageEnglish
JournalNature Chemical Biology
ISSN1552-4450
DOIs
Publication statusPublished - 22.10.2020

Research Areas and Centers

  • Academic Focus: Center for Infection and Inflammation Research (ZIEL)

DFG Research Classification Scheme

  • 201-01 Biochemistry

Coronavirus related work

  • Research on SARS-CoV-2 / COVID-19

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