Issue 10, 2022

Covalent drugs targeting histidine – an unexploited opportunity?

Abstract

Covalent drugs and chemical probes often possess pharmacological advantages over reversible binding ligands, such as enhanced potency and pharmacodynamic duration. The highly nucleophilic cysteine thiol is commonly targeted using acrylamide electrophiles, but the amino acid is rarely present in protein binding sites. Sulfonyl exchange chemistry has expanded the covalent drug discovery toolkit by enabling the rational design of irreversible inhibitors targeting tyrosine, lysine, serine and threonine. Probes containing the sulfonyl fluoride warhead have also been shown to serendipitously label histidine residues in proteins. Histidine targeting is an attractive prospect because the residue is frequently proximal to protein small molecule ligands and the imidazole side chain possesses desirable nucleophilicity. We recently reported the design of cereblon molecular glues to site-selectively modify a histidine in the thalidomide binding site using sulfonyl exchange chemistry. We believe that histidine targeting holds great promise for future covalent drug development and this Opinion highlights these opportunities.

Graphical abstract: Covalent drugs targeting histidine – an unexploited opportunity?

Article information

Article type
Opinion
Submitted
02 aug 2022
Accepted
26 sep 2022
First published
28 sep 2022

RSC Med. Chem., 2022,13, 1121-1126

Covalent drugs targeting histidine – an unexploited opportunity?

J. Che and L. H. Jones, RSC Med. Chem., 2022, 13, 1121 DOI: 10.1039/D2MD00258B

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