Department of Chemistry, The Scripps Research Institute, La Jolla, California 92037, United States.
Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, United States.
J Am Chem Soc. 2020 May 13;142(19):8972-8979. doi: 10.1021/jacs.0c02721. Epub 2020 Apr 29.
The emerging use of covalent ligands as chemical probes and drugs would benefit from an expanded repertoire of cysteine-reactive electrophiles for efficient and diverse targeting of the proteome. Here we use the endogenous electrophile sensor of mammalian cells, the KEAP1-NRF2 pathway, to discover cysteine-reactive electrophilic fragments from a reporter-based screen for NRF2 activation. This strategy identified a series of 2-sulfonylpyridines that selectively react with biological thiols via nucleophilic aromatic substitution (SAr). By tuning the electrophilicity and appended recognition elements, we demonstrate the potential of the 2-sulfonylpyridine reactive group with the discovery of a selective covalent modifier of adenosine deaminase (ADA). Targeting a cysteine distal to the active site, this molecule attenuates the enzymatic activity of ADA and inhibits proliferation of lymphocytic cells. This study introduces a modular and tunable SAr-based reactive group for targeting reactive cysteines in the human proteome and illustrates the pharmacological utility of this electrophilic series.
新兴的共价配体作为化学探针和药物，如果能扩大半胱氨酸反应性亲电试剂的种类，将有利于高效、多样化地靶向蛋白质组。在这里，我们利用哺乳动物细胞内源性亲电传感器 KEAP1-NRF2 通路，从基于报告基因的 NRF2 激活筛选中发现了半胱氨酸反应性亲电片段。该策略从一系列 2-磺酰基吡啶中鉴定出，它们通过亲核芳香取代（SAr）选择性地与生物硫醇反应。通过调整亲电性和亲附识别元件，我们用腺苷脱氨酶（ADA）的选择性共价修饰剂的发现证明了 2-磺酰基吡啶反应基团的潜力。该分子靶向活性位点远端的半胱氨酸，从而减弱 ADA 的酶活性并抑制淋巴细胞的增殖。本研究引入了一种模块化和可调谐的基于 SAr 的反应性基团，用于靶向人类蛋白质组中的反应性半胱氨酸，并说明了该亲电系列的药理学用途。
