共价分子胶降解剂研究进展

Advances in covalent molecular glue degraders

摘要

共价分子胶是靶向蛋白降解（TPD）领域一类具有变革潜力的候选药物。与传统非共价分子胶依赖可逆的蛋白-蛋白界面稳定化不同，共价分子胶通过亲电弹头与靶蛋白或E3泛素连接酶上的亲核残基形成稳定共价键，将动态的三元复合物锁定为功能不可逆的降解体系。这种“识别-锁定”双阶段机制赋予其更持久的靶标占有率、更高的降解效率以及对内源性竞争配体的抗干扰能力。近年来，从天然产物甲异靛的机制再发现，到“模板辅助共价修饰”新范式的建立，再到针对DCAF16 等非经典E3 连接酶的理性设计，共价分子胶正从偶然发现迈向精准 工程。本文系统综述其作用机制、分类逻辑、设计策略、代表性分子及临床转化进展，并深入探讨共价化学带来的特异性、安全性与耐药性等核心挑战，旨在为这一新兴方向提供全景式学术梳理。

Abstract

Covalent molecular glues represent a class of transformative candidate drugs in the field of targeted protein degradation (TPD). Unlike conventional non-covalent molecular glues that rely on reversible stabilization of protein-protein interfaces, covalent molecular glues employ electrophilic warheads to form stable covalent bonds with nucleophilic residues on target proteins or E3 ubiquitin ligases, thereby locking dynamic ternary complexes into functionally irreversible degradation machineries. This 'recognize-and-lock' two-stage mechanism endows covalent molecular glues with prolonged target occupancy, enhanced degradation efficiency, and resilience against competitive endogenous ligands. In recent years, covalent molecular glues have evolved from serendipitous discoveries into precision-engineered modalities, driven by the mechanistic rediscovery of the natural product meisoindigo, the emergence of template-assisted covalent modification, and the rational targeting of non-canonical E3 ligases such as DCAF16. This review systematically summarizes their mechanisms of action, classification logic, design strategies, representative molecules, and progress in clinical translation, while examining in depth the core challenges posed by covalent chemistry-including specificity, safety, and drug resistance with the aim of providing a panoramic academic overview of this emerging direction.

关键词

靶向蛋白降解 / 共价药物 / 共价分子胶 / E3泛素连接酶

Key words

Targeted protein degradation / Covalent drugs / Covalent molecular glues / E3 ubiquitin ligases

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基金资助

国家自然科学基金项目(22521104)