Targeted reversible covalent modification of a noncatalytic lysine of the Krev interaction trapped 1 protein enables site-directed screening for protein-protein interaction inhibitors

Francisco, Karol R., Bruystens, Jessica, Varricchio, Carmine, McCurdy, Sara, Wu, Jian, Lopez-Ramirez, Miguel A., Ginsberg, Mark, Caffrey, Conor R., Brancale, Andrea, Gingras, Alexandre R., Hixon, Mark S. and Ballatore, Carlo 2023. Targeted reversible covalent modification of a noncatalytic lysine of the Krev interaction trapped 1 protein enables site-directed screening for protein-protein interaction inhibitors. ACS Pharmacology & Translational Science 6 (11) , pp. 1651-1658. 10.1021/acsptsci.3c00156

Preview

PDF - Published Version Available under License Creative Commons Attribution. Download (5MB) | Preview

Abstract

The covalent reversible modification of proteins is a validated strategy for the development of probes and candidate therapeutics. However, the covalent reversible targeting of noncatalytic lysines is particularly challenging. Herein, we characterize the 2-hydroxy-1-naphthaldehyde (HNA) fragment as a targeted covalent reversible ligand of a noncatalytic lysine (Lys720) of the Krev interaction trapped 1 (KRIT1) protein. We show that the interaction of HNA with KRIT1 is highly specific, results in prolonged residence time of >8 h, and inhibits the Heart of glass 1 (HEG1)–KRIT1 protein–protein interaction (PPI). Screening of HNA derivatives identified analogs exhibiting similar binding modes as the parent fragment but faster target engagement and stronger inhibition activity. These results demonstrate that HNA is an efficient site-directing fragment with promise in developing HEG1-KRIT1 PPI inhibitors. Further, the aldimine chemistry, when coupled with templating effects that promote proximity, can produce a long-lasting reversible covalent modification of noncatalytic lysines.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Pharmacy
Publisher:	ACS
ISSN:	2575-9108
Date of First Compliant Deposit:	20 March 2024
Last Modified:	20 Mar 2024 11:03
URI:	https://orca.cardiff.ac.uk/id/eprint/166984

Actions (repository staff only)

Edit Item