Discovery and Optimization of Small-Molecule Ligands for V-Domain Ig Suppressor of T-Cell Activation (VISTA)

Gabr, Moustafa T.; Gambhir, Sanjiv S.

doi:10.1021/jacs.0c07276

Cited by 26 publications

(23 citation statements)

References 26 publications

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“…In this study, CA-170 enhanced T cell immune responses and the production of IFN-γ [ 52 ]. CA-170 is in clinical development; however, a recent study showed minimal to no binding of CA-170 to human VISTA by time-resolved fluorescence energy-transfer assay [ 53 ]. In this study, another small-molecule inhibitor, compound III, inhibited VISTA immunosuppressive function, as measured by increased IFN-γ and TNF-α secretion by Jurkat T cells cocultured with VISTA-positive ovarian cancer cell lines.…”

Section: Vista In the Context Of Immunotherapymentioning

confidence: 99%

“…In this study, another small-molecule inhibitor, compound III, inhibited VISTA immunosuppressive function, as measured by increased IFN-γ and TNF-α secretion by Jurkat T cells cocultured with VISTA-positive ovarian cancer cell lines. Docking and mutational analysis showed that compound III interacted with VISTA residues F94, R159, and E157, with a strong hydrophobic interaction with Y69 and H153 [ 53 ]. Thus, small-molecule inhibitors are under development as putative VISTA therapeutics in addition to antagonist and agonist antibodies.…”

Section: Vista In the Context Of Immunotherapymentioning

confidence: 99%

See 1 more Smart Citation

VISTA: A Mediator of Quiescence and a Promising Target in Cancer Immunotherapy

Yuan

Tatineni

Mahoney

et al. 2021

Trends in Immunology

124

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V-domain Ig suppressor of T cell activation (VISTA) is a B7 family member that maintains T cell and myeloid quiescence and is a promising target for combination cancer immunotherapy. During inflammatory challenges, VISTA activity reprograms macrophages towards reduced production of proinflammatory cytokines and increased production of interleukin (IL)-10 and other anti-inflammatory mediators. The interaction of VISTA with its ligands is regulated by pH, and the acidic pH ~6.0 in the tumor microenvironment (TME) facilitates VISTA binding to P-selectin glycoprotein ligand 1 (PSGL-1). Targeting intratumoral pH might be a way to reduce the immunoinhibitory activity of the VISTA pathway and enhance antitumor immune responses. We review differences among VISTA therapeutics under development as candidate immunotherapies, focusing on VISTA binding partners and the unique structural features of this interaction.

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Section: Vista In the Context Of Immunotherapymentioning

confidence: 99%

Section: Vista In the Context Of Immunotherapymentioning

confidence: 99%

VISTA: A Mediator of Quiescence and a Promising Target in Cancer Immunotherapy

Yuan

Tatineni

Mahoney

et al. 2021

Trends in Immunology

124

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“…Additionally, such compounds’ structures can be easily optimized to get the desired biological activity. Previously, only Li et al (2020) and Gabr and Gambhir (2020) reported small-molecule inhibitors against VISTA. Thus, lead-like natural compounds from MPD3 were retrieved ( Figure 1 ).…”

Section: Resultsmentioning

confidence: 99%

Discovery of Novel Inhibitors From Medicinal Plants for V-Domain Ig Suppressor of T-Cell Activation

Muneer

Ahmad

Naz

et al. 2021

Front. Mol. Biosci.

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V-domain Ig suppressor of T cell activation (VISTA) is an immune checkpoint and is a type I transmembrane protein. VISTA is linked to immunotherapy resistance, and it is a potential immune therapeutic target, especially for triple-negative breast cancer. It expresses at a high concentration in regulatory T cells and myeloid-derived suppressor cells, and its functional blockade is found to delay tumor growth. A useful medicinal plant database for drug designing (MPD3), which is a collection of phytochemicals from diverse plant families, was employed in virtual screening against VISTA to prioritize natural inhibitors against VISTA. Three compounds, Paratocarpin K (PubChem ID: 14187087), 3-(1H-Indol-3-yl)-2-(trimethylazaniumyl)propanoate (PubChem ID: 3861164), and 2-[(5-Benzyl-4-ethyl-1,2,4-triazol-3-yl)sulfanylmethyl]-5-methyl-1,3,4-oxadiazole (PubChem ID: 6494266), having binding energies stronger than −6 kcal/mol were found to have two common hydrogen bond interactions with VISTA active site residues: Arg54 and Arg127. The dynamics of the compound–VISTA complexes were further explored to infer binding stability of the systems. Results revealed that the compound 14187087 and 6494266 systems are highly stable with an average RMSD of 1.31 Å. Further affirmation on the results was achieved by running MM-GBSA on the MD simulation trajectories, which re-ranked 14187087 as the top-binder with a net binding energy value of −33.33 kcal/mol. In conclusion, the present study successfully predicted natural compounds that have the potential to block the function of VISTA and therefore can be utilized further in experimental studies to validate their real anti-VISTA activity.

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“…There are two proved ligands of VISTA, one is IGSF11, the other is PSGL1 (P-selectin glycoprotein ligand 1) [ 13 , 14 ]. Besides these, VSIG8, NSC622608 and Galectin 9 may be potential ligands for VISTA [ 15 , 16 ]. The interaction between ligands and receptors may be modulated by the pH in microenvironment [ 14 ], and exert innate and adaptive immune regulation [ 17 , 18 ].…”

Section: Introductionmentioning

confidence: 99%

IGSF11 and VISTA: a pair of promising immune checkpoints in tumor immunotherapy

et al. 2022

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Immunotherapy has become the major treatment for tumors in clinical practice, but some intractable problems such as the low response rate and high rates of immune-related adverse events still hinder the progress of tumor immunotherapy. Hence, it is essential to explore additional immunotherapy treatment targets. In this review, we focus on the structure, expression and expression-related mechanisms, interactions, biological functions and the progress in preclinical/clinical research of IGSF11 and VISTA in tumors. We cover the progress in recent research with this pair of immune checkpoints in tumor immune regulation, proliferation, immune resistance and predictive prognosis. Both IGSF11 and VISTA are highly expressed in tumors and are modulated by various factors. They co-participate in the functional regulation of immune cells and the inhibition of cytokine production. Besides, in the downregulation of IGSF11 and VISTA, both inhibit the growth of some tumors. Preclinical and clinical trials all emphasize the predictive role of IGSF11 and VISTA in the prognosis of tumors, and that the predictive role of the same gene varies from tumor to tumor. At present, further research is proving the enormous potential of IGSF11 and VISTA in tumors, and especially the role of VISTA in tumor immune resistance. This may prove to be a breakthrough to solve the current clinical immune resistance, and most importantly, since research has focused on VISTA but less on IGSF11, IGSF11 may be the next candidate for tumor immunotherapy.

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Discovery and Optimization of Small-Molecule Ligands for V-Domain Ig Suppressor of T-Cell Activation (VISTA)

Cited by 26 publications

References 26 publications

VISTA: A Mediator of Quiescence and a Promising Target in Cancer Immunotherapy

VISTA: A Mediator of Quiescence and a Promising Target in Cancer Immunotherapy

Discovery of Novel Inhibitors From Medicinal Plants for V-Domain Ig Suppressor of T-Cell Activation

IGSF11 and VISTA: a pair of promising immune checkpoints in tumor immunotherapy

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