Discovery and Optimization of Small-Molecule Ligands for V-domain Ig Suppressor of T-cell Activation (VISTA),Journal of the American Chemical Society

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Discovery and Optimization of Small-Molecule Ligands for V-domain Ig Suppressor of T-cell Activation (VISTA)
Journal of the American Chemical Society ( IF 14.4 ) Pub Date : 2020-09-07 , DOI: 10.1021/jacs.0c07276
Moustafa T Gabr _{1,

2} , Sanjiv S Gambhir _{1,

2,

3}

Affiliation

V-domain Ig Suppressor of T-cell Activation (VISTA) is an immune checkpoint that affects the ability of T-cells to attack tumors. A FRET-based high throughput screening identified NSC622608 as the first small-molecule ligand for VISTA. Investigation of the interaction of NSC622608 with VISTA using STD NMR and molecular modeling enabled the identification of a potential binding site in VISTA for NSC622608. Screening NSC622608 against a library of single-point VISTA mutants revealed the key residues in VISTA interacting with NSC622608. Further structural optimization resulted in a lead with submicromolar VISTA binding affinity. The lead compound blocked VISTA signaling in vitro, enhanced T-cell proliferation, and restored T-cell activation in the presence of VISTA-expressing cancer cell lines. This work would enable future development of small molecules targeting VISTA as immunomodulators and imaging probes.

中文翻译：

发现和优化 T 细胞激活的 V 域 Ig 抑制因子 (VISTA) 的小分子配体

V 域 Ig T 细胞激活抑制因子 (VISTA) 是一种免疫检查点，可影响 T 细胞攻击肿瘤的能力。基于 FRET 的高通量筛选将 NSC622608 鉴定为 VISTA 的第一个小分子配体。使用 STD NMR 和分子建模研究 NSC622608 与 VISTA 的相互作用，能够在 VISTA 中鉴定 NSC622608 的潜在结合位点。针对单点 VISTA 突变体库筛选 NSC622608 揭示了 VISTA 中与 NSC622608 相互作用的关键残基。进一步的结构优化导致具有亚微摩尔 VISTA 结合亲和力的先导物。先导化合物在体外阻断 VISTA 信号传导，增强 T 细胞增殖，并在表达 VISTA 的癌细胞系存在的情况下恢复 T 细胞活化。

更新日期：2020-09-07

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