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Developing Covalent Protein Drugs via Proximity-Enabled Reactive Therapeutics.
Cell ( IF 64.5 ) Pub Date : 2020-06-23 , DOI: 10.1016/j.cell.2020.05.028
Qingke Li 1 , Qu Chen 2 , Paul C Klauser 3 , Mengyuan Li 1 , Feng Zheng 4 , Nanxi Wang 3 , Xiaoying Li 5 , Qianbing Zhang 5 , Xuemei Fu 6 , Qian Wang 4 , Yang Xu 2 , Lei Wang 3
Affiliation  

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.



中文翻译:

通过邻近启用的反应疗法开发共价蛋白药物。

与非共价药物相比,小分子共价药物在治疗挑战性疾病方面具有理想的治疗性能。但是,由于蛋白质无法共价结合靶标,因此共价蛋白质药物的潜力尚未得到开发。我们报告了一种近距离激活的反应疗法(PERx)方法来生成共价蛋白药物。通过遗传密码扩展,潜在的生物反应性氨基酸氟硫酸盐-L-酪氨酸(FSY)被纳入人类程序性细胞死亡蛋白-1(PD-1)。只有当PD-1与PD-L1相互作用时,FSY才会选择性地与PD-L1的近端组氨酸反应,从而在体外体内都能使PD-1与PD-L1不可逆地结合。当在免疫人源化小鼠中给药时,与非共价野生型PD-1相比,共价PD-1(FSY)表现出显着更强的抗肿瘤作用,达到了等效于或优于抗PD-L1抗体的治疗功效。PERx应该提供一种通用平台技术,用于将各种相互作用的蛋白质转化为共价结合剂,实现针对生物学研究的特定共价蛋白质靶向,以及常规非共价蛋白质药物无法达到的治疗能力。

更新日期:2020-07-09
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