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Rhenium(V) Complexes as Cysteine-Targeting Coordinate Covalent Warheads.

ABSTRACT: Interest in covalent enzyme inhibitors as therapeutic agents has seen a recent resurgence. Covalent enzyme inhibitors typically possess an organic functional group that reacts with a key feature of the target enzyme, often a nucleophilic cysteine residue. Herein, the application of small, modular Re^V complexes as inorganic cysteine-targeting warheads is described. These metal complexes were found to react with cysteine residues rapidly and selectively. To demonstrate the utility of these Re^V complexes, their reactivity with SARS-CoV-2-associated cysteine proteases is presented, including the SARS-CoV-2 main protease and papain-like protease and human enzymes cathepsin B and L. As all of these proteins are cysteine proteases, these enzymes were found to be inhibited by the Re^V complexes through the formation of adducts. These findings suggest that these Re^V complexes could be used as a new class of warheads for targeting surface accessible cysteine residues in disease-relevant target proteins.

SUBMITTER: Karges J

PROVIDER: S-EPMC9969397 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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Rhenium(V) Complexes as Cysteine-Targeting Coordinate Covalent Warheads.

Karges Johannes J Cohen Seth M SM

Journal of medicinal chemistry 20230208 4

Interest in covalent enzyme inhibitors as therapeutic agents has seen a recent resurgence. Covalent enzyme inhibitors typically possess an organic functional group that reacts with a key feature of the target enzyme, often a nucleophilic cysteine residue. Herein, the application of small, modular Re<sup>V</sup> complexes as inorganic cysteine-targeting warheads is described. These metal complexes were found to react with cysteine residues rapidly and selectively. To demonstrate the utility of th ...[more]

PMID: 36752718

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