共价键
化学
赖氨酸
蛋白质-蛋白质相互作用
配体(生物化学)
组合化学
立体化学
生物化学
氨基酸
受体
有机化学
作者
Karol R. Francisco,Jessica Bruystens,Carmine Varricchio,Sara McCurdy,Jian Wu,Miguel Alejandro Lopez-Ramirez,Mark H. Ginsberg,Conor R. Caffrey,Andrea Brancale,Alexandre R. Gingras,Mark S. Hixon,Carlo Ballatore
出处
期刊:ACS pharmacology & translational science
[American Chemical Society]
日期:2023-10-09
卷期号:6 (11): 1651-1658
标识
DOI:10.1021/acsptsci.3c00156
摘要
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.
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