Senolysis Enabled by Senescent Cell-Sensitive Bioorthogonal Tetrazine Ligation.
Senolysis Enabled by Senescent Cell-Sensitive Bioorthogonal Tetrazine Ligation.
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通过衰老细胞敏感的生物正交四嗪连接实现衰老分解。
DOI：
10.1002/anie.202315425
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发表时间：
2024
期刊：
影响因子：
--
通讯作者：
Wang,Wei
中科院分区：
文献类型：
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作者：
Chang,Mengyang;Dong,Yue;Xu,Hang;Cruickshank-Taylor,AlexisB;Kozora,JacobS;Behpour,Baran;Wang,Wei
尽管清除衰老细胞已被证明可以延缓衰老进程并促进抗癌化疗，但抗衰老药物的开发仍然具有挑战性。在这里，我们报告了一种通过衰老细胞敏感的生物正交四氮卓酮结扎来实现衰老的策略。我们的设计是基于将二氢四嗪(TZ)连接到半乳糖(GAL)部分，半乳糖部分既是衰老相关β-半乳糖苷酶的识别部分，也是控制四嗪活性的笼状基团。GAL-TZ能够有效地点击释放阿特拉斯-环辛烯笼状前药中的荧光半花青碱和阿霉素，以检测和消除衰老的HeLa和A549细胞，而不是非衰老的细胞，衰老指数为16.44。此外，我们利用选择性激活和递送蛋白质降解靶向嵌合体(PROTAC)作为感觉剂的策略。PROTAC前体药物TCO-ARV-771可以被Gal-TZ选择性地激活，并被输送到衰老的HeLa和A549细胞中，以诱导含有溴域的蛋白4的降解。由于PROTAC具有以亚化学计量比和催化的方式降解靶蛋白的独特能力，因此PROTAC可能为干预细胞衰老提供一种有效的途径。这项研究的结果确立了生物正交川芎嗪结扎法是选择性去除衰老细胞的一种可行的策略。
Although the clearance of senescent cells has been proven to slow down the aging process and promote anti‐cancer chemotherapy, the development of senolytics remains challenging. Herein, we report a senolytic strategy enabled by senescent cell‐sensitive bioorthogonal tetrazine ligation. Our design is based on linking dihydrotetrazine (Tz) to a galactose (Gal) moiety that serves both as a recognition moiety for senescence‐associated β‐galactosidase and a caging group for the control of tetrazine activity. Gal‐Tz enables efficient click‐release of a fluorescent hemicyanine and doxorubicin from atrans‐cyclooctene‐caged prodrug to detect and eliminate senescent HeLa and A549 cells over non‐senescent counterparts with a 16.44 senolytic index. Furthermore, we leverage the strategy for the selective activation and delivery of proteolysis‐targeting chimeras (PROTACs) as senolytics. PROTAC prodrug TCO‐ARV‐771 can be selectively activated by Gal‐Tz and delivered into senescent HeLa and A549 cells to induce the degradation of bromodomain‐containing protein 4. Senolytic PROTACs may offer an efficient way for intervention on cell senescence thanks to their unique capacity to degrade target proteins in a sub‐stoichiometric and catalytic fashion. The results of this study establish the bioorthogonal tetrazine ligation approach as a viable strategy for selective removal of senescent cells.