Several novel and effective cysteine targeting (Cys) covalent drugs are in clinical use. However, the target area containing a druggable Cys residue is limited. Therefore, methods for creating covalent drugs that target different residues are being looked for; examples of such ligands include those that target the residues lysine (Lys) and tyrosine (Tyr). Though the histidine (His) side chain is more frequently found in protein binding locations and has higher desirable nucleophilicity, surprisingly limited research has been done to specifically target this residue, and there are not many examples of His-targeting ligands that have been rationally designed. In the current work, we created novel stapled peptides that are intended to target hMcl-1 His 252 covalently. We describe the in vitro (biochemical, NMR, and X-ray) and cellular design and characterization of such agents. Our findings further suggest that the use of electrophiles to specifically target His residues is warranted.

中文翻译：

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靶向 hMcl-1 的组氨酸共价缝合 α 螺旋肽


几种新型有效的半胱氨酸靶向（Cys）共价药物正在临床使用。然而，含有可成药的半胱氨酸残基的目标区域是有限的。因此，正在寻找创建针对不同残基的共价药物的方法；此类配体的实例包括靶向残基赖氨酸(Lys)和酪氨酸(Tyr)的那些。尽管组氨酸 (His) 侧链更常见于蛋白质结合位置，并且具有更高的理想亲核性，但令人惊讶的是，专门针对该残基的研究非常有限，并且合理设计的 His 靶向配体的例子并不多。在当前的工作中，我们创建了新型钉合肽，旨在共价靶向 hMcl-1 His 252。我们描述了此类药物的体外（生化、核磁共振和 X 射线）和细胞设计和表征。我们的研究结果进一步表明，使用亲电子试剂来特异性靶向组氨酸残基是有必要的。