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A Ligand Selection Strategy Identifies Chemical Probes Targeting the Proteases of SARS‐CoV‐2
Author(s) -
Peñalver Lilian,
Schmid Philipp,
Szamosvári Dávid,
Schildknecht Stefan,
Globisch Christoph,
Sawade Kevin,
Peter Christine,
Böttcher Thomas
Publication year - 2021
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.202016113
Subject(s) - proteases , computational biology , proteome , chemistry , ligand (biochemistry) , directed evolution , cysteine , biochemistry , active site , chemical biology , biology , combinatorial chemistry , enzyme , gene , receptor , mutant
Activity‐based probes are valuable tools for chemical biology. However, finding probes that specifically target the active site of an enzyme remains a challenging task. Herein, we present a ligand selection strategy that allows to rapidly tailor electrophilic probes to a target of choice and showcase its application for the two cysteine proteases of SARS‐CoV‐2 as proof of concept. The resulting probes were specific for the active site labeling of 3CL pro and PL pro with sufficient selectivity in a live cell model as well as in the background of a native human proteome. Exploiting the probes as tools for competitive profiling of a natural product library identified salvianolic acid derivatives as promising 3CL pro inhibitors. We anticipate that our ligand selection strategy will be useful to rapidly develop customized probes and discover inhibitors for a wide range of target proteins also beyond corona virus proteases.