Comparative reactivity profiling of cysteine-specific probes by chemoproteomics

Fan Yang , Nan Chen , Fengzhang Wang , Guogeng Jia , Chu Wang
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引用次数: 6

Abstract

Cysteines, as one of the most intrinsically nucleophilic amino acids, play important roles in proteins involved in diverse biological processes. They are also targets of covalent drugs for treating cancers and other diseases. Understanding the cysteine reactivity towards different types of electrophilic reactive groups will contribute to design of cysteine-reactive probes and facilitate the development of cysteine-based covalent drugs. In this study, we systematically evaluated the cysteinome reactivity toward two common electrophilic probes that are based on nucleophilic substitution and Michael addition, respectively, using chemical proteomic strategies. Our profiling results showed that each probe had its own preferential reactivity towards different cysteines and the engagement of the ligand fragments could only be distinguished by the probe with the matching reactive group. Our study highlighted the importance of choosing proper cysteine-reactive probes for screening covalent ligands and provided informative guidance for covalent drug development.

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半胱氨酸特异性探针的化学蛋白质组学反应性比较
半胱氨酸作为最亲核的氨基酸之一,在多种生物过程的蛋白质中起着重要的作用。它们也是治疗癌症和其他疾病的共价药物的靶标。了解半胱氨酸对不同类型的亲电反应基团的反应性将有助于设计半胱氨酸反应性探针,并促进半胱氨酸共价药物的开发。在这项研究中,我们系统地评估了半胱氨酸对两种常见亲电探针的反应性,这两种探针分别基于亲核取代和迈克尔加成,使用化学蛋白质组学策略。我们的分析结果表明,每个探针对不同的半胱氨酸具有自己的优先反应性,并且只有具有匹配反应基团的探针才能区分配体片段的接合。我们的研究强调了选择合适的半胱氨酸反应性探针筛选共价配体的重要性,并为共价药物的开发提供了信息指导。
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来源期刊
Current research in chemical biology
Current research in chemical biology Biochemistry, Genetics and Molecular Biology (General)
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