Identification of active small-molecule modulators targeting the novel immune checkpoint VISTA
Abstract Background 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 acid...
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Online Access: | https://doi.org/10.1186/s12865-021-00446-4 |
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doaj-e1bdf2de240142baa0eccfb33cd92ba92021-08-15T11:07:48ZengBMCBMC Immunology1471-21722021-08-0122111010.1186/s12865-021-00446-4Identification of active small-molecule modulators targeting the novel immune checkpoint VISTATing-ting Li0Jing-wei Jiang1Chen-xin Qie2Chun-xiao Xuan3Xin-lei Hu4Wan-mei Liu5Wen-ting Chen6Jun Liu7Jiangsu Key Lab of Drug Screening, China Pharmaceutical UniversityJiangsu Key Lab of Drug Screening, China Pharmaceutical UniversityJiangsu Key Lab of Drug Screening, China Pharmaceutical UniversityJiangsu Key Lab of Drug Screening, China Pharmaceutical UniversityJiangsu Key Lab of Drug Screening, China Pharmaceutical UniversityJiangsu Key Lab of Drug Screening, China Pharmaceutical UniversityJiangsu Key Lab of Drug Screening, China Pharmaceutical UniversityJiangsu Key Lab of Drug Screening, China Pharmaceutical UniversityAbstract Background 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. Results 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. Conclusions 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.https://doi.org/10.1186/s12865-021-00446-4VISTASmall-molecule modulatorAntagonistHomology modelingVirtual screening |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Ting-ting Li Jing-wei Jiang Chen-xin Qie Chun-xiao Xuan Xin-lei Hu Wan-mei Liu Wen-ting Chen Jun Liu |
spellingShingle |
Ting-ting Li Jing-wei Jiang Chen-xin Qie Chun-xiao Xuan Xin-lei Hu Wan-mei Liu Wen-ting Chen Jun Liu Identification of active small-molecule modulators targeting the novel immune checkpoint VISTA BMC Immunology VISTA Small-molecule modulator Antagonist Homology modeling Virtual screening |
author_facet |
Ting-ting Li Jing-wei Jiang Chen-xin Qie Chun-xiao Xuan Xin-lei Hu Wan-mei Liu Wen-ting Chen Jun Liu |
author_sort |
Ting-ting Li |
title |
Identification of active small-molecule modulators targeting the novel immune checkpoint VISTA |
title_short |
Identification of active small-molecule modulators targeting the novel immune checkpoint VISTA |
title_full |
Identification of active small-molecule modulators targeting the novel immune checkpoint VISTA |
title_fullStr |
Identification of active small-molecule modulators targeting the novel immune checkpoint VISTA |
title_full_unstemmed |
Identification of active small-molecule modulators targeting the novel immune checkpoint VISTA |
title_sort |
identification of active small-molecule modulators targeting the novel immune checkpoint vista |
publisher |
BMC |
series |
BMC Immunology |
issn |
1471-2172 |
publishDate |
2021-08-01 |
description |
Abstract Background 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. Results 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. Conclusions 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. |
topic |
VISTA Small-molecule modulator Antagonist Homology modeling Virtual screening |
url |
https://doi.org/10.1186/s12865-021-00446-4 |
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