Li Qingke, Chen Qu, Klauser Paul C, Li Mengyuan, Zheng Feng, Wang Nanxi, Li Xiaoying, Zhang Qianbing, Fu Xuemei, Wang Qian, Xu Yang, Wang Lei
Cancer Research Institute, Guangdong Provincial Key Laboratory of Cancer Immunotherapy, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong 510515, China; Hangzhou Research Institute of Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Hangzhou 310018, China.
Cancer Research Institute, Guangdong Provincial Key Laboratory of Cancer Immunotherapy, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong 510515, China; The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong 518033, China.
Cell. 2020 Jul 9;182(1):85-97.e16. doi: 10.1016/j.cell.2020.05.028. Epub 2020 Jun 23.
Small molecule covalent drugs provide desirable therapeutic properties over noncovalent ones for treating challenging diseases. The potential of covalent protein drugs, however, remains unexplored due to protein's inability to bind targets covalently. We report a proximity-enabled reactive therapeutics (PERx) approach to generate covalent protein drugs. Through genetic code expansion, a latent bioreactive amino acid fluorosulfate-L-tyrosine (FSY) was incorporated into human programmed cell death protein-1 (PD-1). Only when PD-1 interacts with PD-L1 did the FSY react with a proximal histidine of PD-L1 selectively, enabling irreversible binding of PD-1 to only PD-L1 in vitro and in vivo. When administrated in immune-humanized mice, the covalent PD-1(FSY) exhibited strikingly more potent antitumor effect over the noncovalent wild-type PD-1, attaining therapeutic efficacy equivalent or superior to anti-PD-L1 antibody. PERx should provide a general platform technology for converting various interacting proteins into covalent binders, achieving specific covalent protein targeting for biological studies and therapeutic capability unattainable with conventional noncovalent protein drugs.
小分子共价药物在治疗疑难疾病方面比非共价药物具有更理想的治疗特性。然而，由于蛋白质无法与靶点共价结合，共价蛋白质药物的潜力仍未得到探索。我们报道了一种基于邻近效应的反应性治疗方法（PERx）来生成共价蛋白质药物。通过遗传密码扩展，一种潜在的生物反应性氨基酸氟硫酸-L-酪氨酸（FSY）被整合到人类程序性细胞死亡蛋白1（PD-1）中。只有当PD-1与PD-L1相互作用时，FSY才会与PD-L1的近端组氨酸选择性反应，从而在体外和体内实现PD-1仅与PD-L1的不可逆结合。在免疫人源化小鼠中给药时，共价PD-1（FSY）比非共价野生型PD-1表现出显著更强的抗肿瘤作用，达到了与抗PD-L1抗体相当或更优的治疗效果。PERx应该为将各种相互作用的蛋白质转化为共价结合剂提供一个通用的平台技术，实现特定的共价蛋白质靶向，用于生物学研究以及传统非共价蛋白质药物无法企及的治疗能力。
