SuFEx 使能的人中性粒细胞弹性蛋白酶共价抑制剂的无偏倚发现。
SuFEx-enabled, agnostic discovery of covalent inhibitors of human neutrophil elastase.
机构信息
Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037.
Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037.
出版信息
Proc Natl Acad Sci U S A. 2019 Sep 17;116(38):18808-18814. doi: 10.1073/pnas.1909972116. Epub 2019 Sep 4.
Abstract
Sulfur fluoride exchange (SuFEx) has emerged as the new generation of click chemistry. We report here a SuFEx-enabled, agnostic approach for the discovery and optimization of covalent inhibitors of human neutrophil elastase (hNE). Evaluation of our ever-growing collection of SuFExable compounds toward various biological assays unexpectedly revealed a selective and covalent hNE inhibitor: benzene-1,2-disulfonyl fluoride. Synthetic derivatization of the initial hit led to a more potent agent, 2-(fluorosulfonyl)phenyl fluorosulfate with IC 0.24 μM and greater than 833-fold selectivity over the homologous neutrophil serine protease, cathepsin G. The optimized, yet simple benzenoid probe only modified active hNE and not its denatured form.
摘要
硫氟交换（SuFEx）已成为新一代点击化学。我们在此报告了一种基于 SuFEx 的、通用的方法，用于发现和优化人中性粒细胞弹性蛋白酶（hNE）的共价抑制剂。对我们不断增长的 SuFEx 化合物库进行各种生物测定的评估，出人意料地揭示了一种对人中性粒细胞弹性蛋白酶具有选择性和共价抑制作用的化合物：苯-1,2-二磺酰氟。对初始命中化合物的合成衍生化得到了一种更有效的化合物 2-(氟磺酰基)苯基氟磺酸盐，其对同源的中性粒细胞蛋白酶、组织蛋白酶 G 的 IC0.24 μM，选择性大于 833 倍。经过优化的、简单的苯类探针仅修饰活性 hNE，而不修饰其变性形式。
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