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结构引导发现PD-1/PD-L1相互作用抑制剂:通过计算辅助的菌体显示工程来设计,选和优化

Tien-Sheng Tseng¹, Chao-Chang Lee², Po-Juei Chen^1,2

¹Institute of Molecular Biology, National Chung Hsing University, Taichung 40202, Taiwan.

Journal of chemical information and modeling

|February 15, 2024

概括

研究人员开发了一种新型的抑制剂B8.4,以破坏PD-1/PD-L1相互作用,为癌症免疫疗法提供了一个有前途的新途径,其副作用比目前的治疗方法少.

科学领域:

免疫学免疫学免疫学
在瘤学瘤学.
药物发现药物发现药物发现

背景情况:

癌症免疫疗法利用免疫系统对抗瘤,PD-1/PD-L1检查点是关键目标.
目前的PD-1/PD-L1单克隆抗体抑制剂具有显著的副作用,需要新的治疗策略.

研究的目的:

设计和开发针对PD-1/PD-L1免疫检查点的新型抑制剂.
识别具有对PD-1高亲和力的强抑制剂,并评估它们在破坏PD-1/PD-L1相互作用方面的有效性.

主要方法:

结构驱动的菌体显示工程和计算优化被用于设计抑制剂.
包括BetaPb在内的库使用酶相关的免疫吸收试验,均质时间解析光和生物层干扰仪进行了选.
评估了类的结合亲和力和抑制潜力,如B8及其变体,并与现有的抑制剂进行了比较.

主要成果:

一种新型的抑制剂B8.4被确定具有破坏PD-1/PD-L1相互作用的强大能力.
B8.4对PD-1具有强大的结合亲和力 (Kd = 0.1 μM) 和高衰减效率 (EC50 = 0.1 μM).
在破坏PD-1/PD-L1相互作用方面,B8.4的性能优于已知的抑制剂PL120131.

结论:

B8.4显示出显著的潜力,作为开发基于的新型抗瘤剂的基础.
这项研究强调了抑制剂在癌症免疫治疗中的价值,为基于抗体的治疗提供了一个有希望的替代方案.
进一步修改B8.4可能会导致癌症治疗的先进疗法.

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Protein-protein Interfaces

Protein-protein Interfaces

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