Covalent drugs provide pharmacodynamic and pharmacokinetic advantages over reversible agents. However, covalent strategies have been developed mostly to target cysteine (Cys) residues, which are rarely found in binding sites. Among other nucleophilic residues that could be in principle used for the design of covalent drugs, histidine (His) has not been given proper attention despite being in principle an attractive residue to pursue but underexplored. Aryl fluorosulfates, a mild electrophile that is very stable in biological media, have been recently identified as possible electrophiles to react with the side chains of Lys; however, limited studies are available on aryl fluorosulfates’ ability to target His residues. We demonstrate that proper incorporation of an aryl fluorosulfate juxtaposing the electrophile with a His residue can be used to afford rapid optimizations of His-covalent agents. As an application, we report on His-covalent BH3 mimetics targeting His224 of Mcl-1.

中文翻译：

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芳基氟硫酸盐共价靶向组氨酸残基：在 Mcl-1 BH3 模拟物中的应用


与可逆药物相比，共价药物具有药效学和药代动力学优势。然而，共价策略主要针对半胱氨酸 （Cys） 残基开发，而半胱氨酸 （Cys） 残基在结合位点中很少见。在原则上可用于共价药物设计的其他亲核残基中，组氨酸 （His） 尽管原则上是一种有吸引力的残基，但尚未得到充分开发。芳基氟硫酸盐是一种在生物介质中非常稳定的温和亲电试剂，最近已被确定为可能与 Lys 的侧链反应的亲电试剂;然而，关于芳基氟硫酸盐靶向 His 残基的能力的研究有限。我们证明，将亲电试剂与 His 残基并置的芳基氟硫酸盐的适当掺入可用于快速优化 His 共价试剂。作为一项应用，我们报道了靶向 Mcl-1 的 His224 的 His 共价 BH3 模拟物。