用于共价探针和治疗开发的反应性化学。
Reactive chemistry for covalent probe and therapeutic development.
机构信息
Department of Chemistry, University of Virginia, Charlottesville, VA 22904, USA.
Department of Chemistry, University of Virginia, Charlottesville, VA 22904, USA; Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA22908, USA; Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA 22908, USA; University of Virginia Cancer Center, University of Virginia, Charlottesville, VA 22903, USA.
出版信息
Trends Pharmacol Sci. 2022 Mar;43(3):249-262. doi: 10.1016/j.tips.2021.12.002. Epub 2022 Jan 6.
Bioactive small molecules that form covalent bonds with a target protein are important tools for basic research and can be highly effective drugs. This review highlights reactive groups found in a collection of thiophilic and oxophilic drugs that mediate pharmacological activity through a covalent mechanism of action (MOA). We describe the application of advanced proteomic and bioanalytical methodologies for assessing selectivity of these covalent agents to guide and inspire the search for additional electrophiles suitable for covalent probe and therapeutic development. While the emphasis is on chemistry for modifying catalytic serine, threonine or cysteine residues, we devote a substantial fraction of the review to a collection of exploratory reactive groups of understudied residues on proteins.
与靶蛋白形成共价键的生物活性小分子是基础研究的重要工具，并且可以成为非常有效的药物。这篇综述强调了在一组亲硫和亲氧药物中发现的反应基团，这些药物通过共价作用机制（MOA）介导药理活性。我们描述了先进的蛋白质组学和生物分析方法在评估这些共价试剂的选择性方面的应用，以指导和激发对适合共价探针和治疗开发的其他亲电试剂的搜索。虽然重点是用于修饰催化丝氨酸、苏氨酸或半胱氨酸残基的化学，但我们在综述中很大一部分专门讨论了蛋白质中研究较少的残基的一组探索性反应基团。
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