Tamura Tomonori, Kawano Masaharu, Hamachi Itaru
Graduate School of Engineering, Department of Synthetic Chemistry and Biological Chemistry, Kyoto University, Katsura, Nishikyo-ku, Kyoto 615-8510, Japan.
Exploratory Research for Advanced Technology (ERATO), Japan Science and Technology Agency (JST), 5 Sanbancho, Chiyoda-ku, Tokyo 102-0075, Japan.
Chem Rev. 2025 Jan 22;125(2):1191-1253. doi: 10.1021/acs.chemrev.4c00745. Epub 2025 Jan 7.
The term "undruggable" refers to proteins or other biological targets that have been historically challenging to target with conventional drugs or therapeutic strategies because of their structural, functional, or dynamic properties. Drugging such undruggable targets is essential to develop new therapies for diseases where current treatment options are limited or nonexistent. Thus, investigating methods to achieve such drugging is an important challenge in medicinal chemistry. Among the numerous methodologies for drug discovery, covalent modification of therapeutic targets has emerged as a transformative strategy. The covalent attachment of diverse functional molecules to targets provides a powerful platform for creating highly potent drugs and chemical tools as well the ability to provide valuable information on the structures and dynamics of undruggable targets. In this review, we summarize recent examples of chemical methods for the covalent modification of proteins and other biomolecules for the development of new therapeutics and to overcome drug discovery challenges and highlight how such methods contribute toward the drugging of undruggable targets. In particular, we focus on the use of covalent chemistry methods for the development of covalent drugs, target identification, drug screening, artificial modulation of post-translational modifications, cancer specific chemotherapies, and nucleic acid-based therapeutics.
“不可成药”一词指的是由于其结构、功能或动力学特性，在历史上一直难以用传统药物或治疗策略进行靶向的蛋白质或其他生物靶点。针对此类不可成药靶点开发药物对于为当前治疗选择有限或不存在的疾病研发新疗法至关重要。因此，研究实现此类药物研发的方法是药物化学领域的一项重要挑战。在众多药物发现方法中，对治疗靶点进行共价修饰已成为一种变革性策略。将各种功能分子共价连接到靶点上，为创造高效能药物和化学工具提供了一个强大的平台，同时也能够提供有关不可成药靶点的结构和动力学的有价值信息。在本综述中，我们总结了近期用于蛋白质和其他生物分子共价修饰的化学方法的实例，这些方法用于开发新疗法以及克服药物发现挑战，并强调这些方法如何有助于实现对不可成药靶点的药物研发。特别是，我们重点关注共价化学方法在共价药物开发、靶点鉴定、药物筛选、翻译后修饰的人工调控、癌症特异性化疗以及基于核酸的治疗中的应用。
