Sun Hui, Wang Cong, Li Xiaona, Lü Zirui, Li Kebin, Hu Hengjie, Xu Ping, Xiao Yu, Niu Yan
Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China.
Department of Medical Oncology and Radiation Sickness, Peking University Third Hospital, Beijing 100191, People's Republic of China.
ACS Med Chem Lett. 2024 Oct 14;15(11):1852-1859. doi: 10.1021/acsmedchemlett.4c00274. eCollection 2024 Nov 14.
Targeted protein degradation has been emerging as a promising strategy for drug design and a useful tool for the research of intracellular protein function by specifically downregulating the protein level via promoted degradation. Aside from proteolysis targeting chimeras (PROTAC) that utilize a specific E3 ligase ligand as a tag to recruit polyubiquitin onto the targeted protein and subsequently induce degradation, BocArg was also reported an efficient tag to induce degradation through directly localizing the protein to the 20S proteasome. Based on the similarity of BocLys and BocArg, we identified that BocLys also efficiently induced targeted protein degradation, taking glutathione S-transferase as an example. We found that BocLys-linked ethacrynic acid was able to dose-dependently downregulate the target protein in a mechanism distinct to BocArg.
靶向蛋白质降解已成为一种有前景的药物设计策略，并且是通过促进降解特异性下调蛋白质水平来研究细胞内蛋白质功能的有用工具。除了利用特定E3连接酶配体作为标签将多聚泛素募集到靶向蛋白质上并随后诱导降解的蛋白酶靶向嵌合体（PROTAC）之外，据报道BocArg也是一种通过将蛋白质直接定位到20S蛋白酶体来诱导降解的有效标签。基于BocLys和BocArg的相似性，我们以谷胱甘肽S-转移酶为例，确定BocLys也能有效诱导靶向蛋白质降解。我们发现，与BocLys连接的依他尼酸能够以与BocArg不同的机制剂量依赖性地下调靶蛋白。
