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基于结构的虚拟查识别了在细胞和粘膜模型中抑制T细胞共刺激的强效CD28抑制剂

Saurabh Upadhyay¹, Valerij Talagayev², Sungwoo Cho¹

¹Department of Radiology, Molecular Imaging Innovations Institute (MI3), Weill Cornell Medicine, New York, NY, 10065, USA.

European journal of medicinal chemistry

|September 24, 2025

概括

研究人员发现了一种名为22VS的小分子,它阻断了CD28共刺激,这是对PD-1和CTLA-4抑制剂等癌症免疫疗法耐药性的关键机制. 这为提高癌症治疗效率提供了一种新策略.

科学领域:

免疫学免疫学免疫学
药理学药理学是指药理学的学科.
结构生物学结构生物学

背景情况:

针对PD-1和CTLA-4的免疫检查点抑制剂 (ICI) 是关键的癌症疗法.
对ICI的耐药性往往涉及补偿性CD28代刺激,限制了治疗的有效性.
需要新的策略来克服ICI耐药性并改善患者的治疗结果.

研究的目的:

发现和验证CD28.8的小分子对抗剂.
开发一种药理方法来克服对PD-1和CTLA-4阻塞的抗性.
确定一种用于调节癌症免疫治疗中T细胞反应的化合物.

主要方法:

基于结构的虚拟选超过700万个化合物.
分子动力学和基于Pyrod的水图绘制,以确定CD28.8上的可用药物的位置.
生物物理结合试验 (TRIC,MST) 和功能试验 (ELISA,NanoBit) 用于化合物验证.
细胞测试以评估抑制CD28-B7相互作用和细胞因子产生.
化合物的药理动力学和安全性分析.

主要成果:

在CD28上识别了一个神秘的脂友峡谷作为可用药物的目标.
发现化合物22VS作为一种强效和选择性的小分子CD28抗剂.
22VS显示了亚微粒度IC50值,并抑制了关键的促炎细胞因子 (IFN-γ,IL-2,TNF-α).
22VS模仿了针对CD28的生物FR104的活性,并显示出良好的安全性和药理动力学特征.
CD28被验证为一种可用药物的免疫治疗检查点.

结论:

小分子CD28抗剂,以22VS为例,代表了克服对PD-1和CTLA-4抑制剂耐药性的有希望的策略.
这种方法在增强癌症免疫疗法以及治疗自身免疫性疾病和管理移植方面具有潜在的应用.
22VS是对调节T细胞反应和改善治疗结果的验证主要候选者.

关键词:

制药学模型的建模.蛋白蛋白相互作用抑制剂蛋白蛋白相互作用抑制剂基于结构的药物设计.同时刺激T细胞共刺激.虚拟选是一个虚拟的选.

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