Targeted Reversible Covalent Modification of a Noncatalytic Lysine of the Krev Interaction Trapped 1 Protein Enables Site-Directed Screening for Protein-Protein Interaction Inhibitors.
Targeted Reversible Covalent Modification of a Noncatalytic Lysine of the Krev Interaction Trapped 1 Protein Enables Site-Directed Screening for Protein-Protein Interaction Inhibitors.
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DOI：
10.1021/acsptsci.3c00156
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发表时间：
2023-10
影响因子：
6
通讯作者：
Karol R. Francisco;J. Bruystens;C. Varricchio;Sara McCurdy;Jian Wu;M. Lopez-Ramirez;Mark Ginsberg;Conor R. Caffrey;Andrea Brancale;Alexandre R. Gingras;Mark S. Hixon;C. Ballatore
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作者：
Karol R. Francisco;J. Bruystens;C. Varricchio;Sara McCurdy;Jian Wu;M. Lopez-Ramirez;Mark Ginsberg;Conor R. Caffrey;Andrea Brancale;Alexandre R. Gingras;Mark S. Hixon;C. Ballatore
蛋白质的共价可逆修饰是开发探针和候选治疗方法的有效策略。然而，共价可逆靶向非催化赖氨酸是特别具有挑战性的。在这里，我们将2-羟基-1-萘醛（HNA）片段表征为Krev相互作用捕获1 （KRIT1）蛋白的非催化赖氨酸（Lys720）的靶向共价可逆配体。我们发现，HNA与KRIT1的相互作用具有高度特异性，导致滞留时间延长bbbb8 h，并抑制玻璃心1 (HEG1)-KRIT1蛋白-蛋白相互作用（PPI）。筛选海航衍生物发现类似物具有与母体片段相似的结合模式，但更快的靶向结合和更强的抑制活性。这些结果表明，HNA是一个有效的位点定向片段，有望开发HEG1-KRIT1 PPI抑制剂。此外，醛胺化学，当与促进接近的模板效应相结合时，可以产生非催化赖氨酸的持久可逆共价修饰。
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.