Department of Chemistry, Boston College, Chestnut Hill, MA 02467, United States.
Department of Chemistry, Boston College, Chestnut Hill, MA 02467, United States.
Curr Opin Chem Biol. 2019 Jun;50:29-36. doi: 10.1016/j.cbpa.2019.02.010. Epub 2019 Mar 18.
The recognition that only a small percentage of known human gene products are druggable using traditional modes of non-covalent ligand design, has led to a resurgence in targeted covalent inhibitors. Covalent inhibitors offer advantages over non-covalent inhibitors in engaging otherwise challenging targets. Reactive cysteine residues on proteins are a common target for covalent inhibitors, whereby the high nucleophilicity of the cysteine thiol under physiological conditions provides an ideal anchoring site for electrophilic small molecules. A chemical-proteomic platform, termed isoTOP-ABPP, allows for profiling cysteine reactivity in complex proteomes and is one of many techniques that can aid in two aspects of the covalent-inhibitor development process: (1) to identify functional cysteines that lead to modulation of protein activity through covalent modification; and, (2) to determine cellular targets and evaluate promiscuity of electrophilic fragments, small molecules, and natural products. Herein, we discuss recent advances in isoTOP-ABPP and potential applications of this technology in the drug-discovery pipeline.
只有一小部分已知的人类基因产物可以通过传统的非共价配体设计方式进行药物研发，这一认识促使靶向共价抑制剂的研究再次兴起。与非共价抑制剂相比，共价抑制剂在与其他具有挑战性的靶标结合方面具有优势。蛋白质上的反应性半胱氨酸残基是共价抑制剂的常见靶标，生理条件下半胱氨酸巯基的高亲核性为亲电子小分子提供了理想的锚定位点。一种称为 isoTOP-ABPP 的化学蛋白质组学平台可用于对复杂蛋白质组中的半胱氨酸反应性进行分析，这是许多可辅助共价抑制剂研发过程中两个方面的技术之一：(1) 鉴定通过共价修饰导致蛋白质活性调节的功能半胱氨酸；以及，(2) 确定细胞靶标并评估亲电片段、小分子和天然产物的广谱性。本文讨论了 isoTOP-ABPP 的最新进展及其在药物发现管道中的潜在应用。
