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Using sulfuramidimidoyl fluorides that undergo sulfur(VI) fluoride exchange for inverse drug discovery.
Nature Chemistry ( IF 19.2 ) Pub Date : 2020-08-31 , DOI: 10.1038/s41557-020-0530-4
Gabriel J Brighty 1, 2 , Rachel C Botham 1, 2, 3 , Suhua Li 1, 4 , Luke Nelson 1 , David E Mortenson 1, 2, 5 , Gencheng Li 1 , Christophe Morisseau 6, 7 , Hua Wang 1, 8 , Bruce D Hammock 6, 7 , K Barry Sharpless 1, 9 , Jeffery W Kelly 1, 2, 9
Affiliation  

Drug candidates that form covalent linkages with their target proteins have been underexplored compared with the conventional counterparts that modulate biological function by reversibly binding to proteins, in part due to concerns about off-target reactivity. However, toxicity linked to off-target reactivity can be minimized by using latent electrophiles that only become activated towards covalent bond formation on binding a specific protein. Here we study sulfuramidimidoyl fluorides, a class of weak electrophiles that undergo sulfur(vi) fluoride exchange chemistry. We show that equilibrium binding of a sulfuramidimidoyl fluoride to a protein can allow nucleophilic attack by a specific amino acid side chain, which leads to conjugate formation. We incubated small molecules, each bearing a sulfuramidimidoyl fluoride electrophile, with human cell lysate, and the protein conjugates formed were identified by affinity chromatography–mass spectrometry. This inverse drug discovery approach identified a compound that covalently binds to and irreversibly inhibits the activity of poly(ADP-ribose) polymerase 1, an important anticancer target in living cells.



中文翻译:

使用经过硫(VI)氟化物交换的磺酰胺基亚氨基酰氟进行反向药物发现。

与通过其可逆地结合蛋白质来调节生物学功能的常规对应物相比,与它们的靶蛋白形成共价键的候选药物的开发还不够充分,部分原因是担心脱靶反应性。但是,与脱靶反应性相关的毒性可以通过使用仅在结合特定蛋白质时才朝共价键形成激活的潜在亲电试剂来最小化。我们在这里学习sulfuramidimidoyl氟化物,一类是经过硫磺弱亲电()氟化物交换化学。我们表明,磺酰胺基亚氨基氟化物与蛋白质的平衡结合可以使特定氨基酸侧链发生亲核攻击,从而导致共轭物形成。我们将小分子与人细胞裂解液一起孵育,每个小分子带有一个磺酰胺基亚氨基氟化氟亲电体,并通过亲和色谱-质谱法鉴定了形成的蛋白质结合物。这种反向药物发现方法确定了一种化合物,该化合物与活细胞中重要的抗癌靶标聚(ADP-核糖)聚合酶1共价结合并不可逆地抑制其活性。

更新日期:2020-10-19
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