Xu Hanlin, Yao Qingxin, Hu Xiaoqian, Zheng Debin, Ren Chao, Ren Zhibin, Gao Yuan
State Key Laboratory of Chemical Resource Engineering, MOE Key Lab of Biomedical Materials of Natural Macromolecules, Beijing University of Chemical Technology, Beijing, 100029, China.
Medicine Medical Innovation Research Division of the Chinese PLA General Hospital, Beijing, 100853, China.
Angew Chem Int Ed Engl. 2025 Jul;64(27):e202502922. doi: 10.1002/anie.202502922. Epub 2025 May 2.
Covalent drugs have experienced a revival in recent decades due to their advantageous pharmacodynamic profiles and targeting of "undruggable" proteins. However, balancing selectivity, reactivity, and potency is essential for safe and effective drugs. Here, we employ a cell-selective bioorthogonal prodrug design to enhance the selectivity for covalent inhibitors without compromising the reactivity and potency. The upregulation of phosphatase and integrin facilitates the formation of enzyme-instructed supramolecular assemblies (EISA) on the cancer cell membrane. These assemblies localize bioorthogonal reaction handles tetrazine (Tz), which liberate Melphalan from its bioorthogonal prodrug TCO-Mel. The TCO modification disrupts the LAT1-mediated transportation, reducing cellular permeability of TCO-Mel and the corresponding cytotoxicity to normal cells. Although the cell-selective on-membrane assemblies directed prodrug activation restores Melphalan influx to inhibit cancer cell growth. This prodrug activation strategy further demonstrates potent tumor suppression with satisfactory biocompatibility in vivo. Overall, we extend the scope of bioorthogonal prodrug design for covalent drugs via regulating cellular influx of active pharmaceutical ingredients (APIs).
近几十年来，共价药物因其有利的药效学特性以及对“不可成药”蛋白质的靶向作用而再度兴起。然而，平衡选择性、反应活性和效力对于安全有效的药物至关重要。在此，我们采用细胞选择性生物正交前药设计来提高共价抑制剂的选择性，同时不影响其反应活性和效力。磷酸酶和整合素的上调促进了癌细胞膜上酶指导的超分子组装体（EISA）的形成。这些组装体将生物正交反应基团四嗪（Tz）定位，从而使美法仑从其生物正交前药TCO-美法仑中释放出来。TCO修饰破坏了LAT1介导的转运，降低了TCO-美法仑的细胞通透性以及对正常细胞的相应细胞毒性。尽管细胞选择性的膜上组装体指导的前药激活恢复了美法仑的内流以抑制癌细胞生长。这种前药激活策略在体内进一步证明了强大的肿瘤抑制作用以及令人满意的生物相容性。总体而言，我们通过调节活性药物成分（API）的细胞内流，扩展了共价药物生物正交前药设计的范围。
