Promising reversible protein inhibitors kept on target

Hacker, Stephan M.

doi:10.1038/d41586-022-00692-5

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14 March 2022

Promising reversible protein inhibitors kept on target

Compounds that form reversible covalent bonds with lysine amino-acid residues in proteins have high potential for drug discovery. A chemical group has been reported that prolongs the time for which such compounds bind to their targets.

Stephan M. Hacker⁰

Stephan M. Hacker
1. Stephan M. Hacker is at the Leiden Institute of Chemistry, Leiden University, 2333 CC Leiden, the Netherlands.
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In the past few years, drug-discovery researchers have become increasingly interested in covalent inhibitors — compounds that bind and inhibit a target protein by forming a covalent bond to it¹^,², rather than binding through non-covalent interactions alone, as most conventional small-molecule drugs do. A subclass of compounds known as reversible covalent inhibitors has particular promise, but the chemical groups available for their design can pose the challenge that they do not bind to proteins for long enough to exert an effect. Writing in the Journal of the American Chemical Society, Reja et al.³ report a chemically reactive group that targets commonly found lysine amino-acid residues in proteins, and that prolongs the time spent by reversible covalent inhibitors at their binding sites.

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Nature 603, 583-584 (2022)

doi: https://doi.org/10.1038/d41586-022-00692-5

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