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Updated: Dec 9, 2025

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发现和优化小分子对T细胞激活的V域Ig抑制剂 (VISTA)

Moustafa T Gabr^1,2, Sanjiv S Gambhir^1,2,3

¹Bio-X Program and Molecular Imaging Program at Stanford (MIPS), Stanford University, Stanford, California 94305, United States.

Journal of the American Chemical Society

|September 7, 2020

概括

研究人员发现NSC622608,这是第一个针对VISTA免疫检查点的小分子. 这种分子增强了T细胞对瘤的激活,为新的癌症免疫疗法铺平了道路.

科学领域:

免疫学
药理学
结构生物学

背景情况:

抑制T细胞激活的V域Ig (VISTA) 是一种关键的免疫检查点蛋白,可以抑制T细胞介导的抗瘤反应.
针对免疫检查点是癌症免疫治疗的一个有希望的策略.

研究的目的:

为了识别和描述VISTA的小分子配体.
为了阐明小分子和VISTA之间的结合相互作用.
开发针对VISTA的小分子作为癌症治疗的潜在免疫调节剂.

主要方法:

使用Förster共振能量转移 (FRET) 识别VISTA连体的高通量选.
和转移差核磁共振 (STD NMR) 和分子建模以确定结合部位和相互作用.
对VISTA单点突变体进行查,以确定关键的相互作用残留物.
在体外测试以评估化合物对T细胞激活的功能作用.

主要成果:

NSC622608被确定为VISTA的第一个小分子配体.
性病核磁共振和分子建模揭示了潜在的结合部位和关键的相互作用残留物.
结构优化产生了具有亚微分子VISTA结合亲和力的化合物.
在VISTA表达癌细胞的存在下,化合物抑制了VISTA信号传递,增强了T细胞的增殖,并恢复了T细胞的激活.

结论:

发现NSC622608和随后的优化为VISTA提供了一种新的小分子方法.
这些发现使VISTA针对癌症免疫治疗和成像探针的小分子的未来发展成为可能.

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