Identification of active small-molecule modulators targeting the novel immune checkpoint VISTA.
Identification of active small-molecule modulators targeting the novel immune checkpoint VISTA.
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DOI：
10.1186/s12865-021-00446-4
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发表时间：
2021-08-11
期刊：
影响因子：
3
通讯作者：
Liu J
中科院分区：
文献类型：
--
作者：
Li TT;Jiang JW;Qie CX;Xuan CX;Hu XL;Liu WM;Chen WT;Liu J
癌症免疫疗法作为一种治疗癌症的新方法越来越受欢迎。作为B7家族的一员，V结构域免疫球蛋白T细胞活化抑制因子（VISTA）是一种新型免疫检查点，可调节广谱免疫反应。VISTA是P-选择素糖蛋白配体-I（PSGL-1）的酸性pH选择性配体。CA-170是一类VISTA/PD-L1的小分子双重拮抗剂，由Aurigene Discovery Technologies Limited和Curis，Inc.合作开发。目前正在进行I期临床试验。在这项研究中，我们开发了VISTA 3D结构的同源建模和随后的VISTA小分子命中配体的虚拟筛选。对接配体与VISTA蛋白的结合姿势的可视化表明一些小分子化合物靶向VISTA。通过体外功能研究研究拮抗剂破坏免疫检查点VISTA途径的能力。通过虚拟筛选获得VISTA亲和活性分子，并在细胞水平上测定化合物对VISTA的拮抗活性。我们报道了一种具有高VISTA亲和力的小分子拮抗剂，为开发VISTA靶向小分子化合物用于癌症免疫治疗提供了思路。在线版本包含补充材料，可通过10.1186/s12865-021-00446-4获得。
Cancer immunotherapy has gained increasing popularity as a novel approach to treat cancer. A member of the B7 family, V-domain immunoglobulin suppressor of T-cell activation (VISTA) is a novel immune checkpoint that regulates a broad spectrum of immune responses. VISTA is an acidic pH-selective ligand for P-selectin glycoprotein ligand-1(PSGL-1). CA-170, a first-in-class small-molecule dual antagonist of VISTA/PD-L1, was collaboratively developed by Aurigene Discovery Technologies Limited and Curis, Inc. It is currently in Phase I clinical trial. In this study, we develop homology modeling for the VISTA 3D structure and subsequent virtual screening for VISTA small-molecule hit ligands. Visualization of the binding postures of docked ligands with the VISTA protein indicates that some small molecular compounds target VISTA. The ability of antagonist to disrupt immune checkpoint VISTA pathways was investigated though functional studies in vitro. Affinity active molecule for VISTA was obtained through virtual screening, and the antagonist compound activity to VISTA was assayed in cellular level. We reported a small molecule with high VISTA affinity as antagonist, providing ideas for development VISTA-targeted small molecule compound in cancer immunotherapy. The online version contains supplementary material available at 10.1186/s12865-021-00446-4.
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影响因子：
82.9
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Gao J;Ward JF;Pettaway CA;Shi LZ;Subudhi SK;Vence LM;Zhao H;Chen J;Chen H;Efstathiou E;Troncoso P;Allison JP;Logothetis CJ;Wistuba II;Sepulveda MA;Sun J;Wargo J;Blando J;Sharma P
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