M351-0056 is a novel low MW compound modulating the actions of the immune-checkpoint protein VISTA

Abstract

Background and Purpose: The protein V-domain immunoglobulin suppressor of T-cell activation (VISTA) is a novel immune-checkpoint molecule that belongs to the B7 family and regulates a broad spectrum of immune responses. So far, low MW compounds targeting VISTA for the treatment of autoimmune diseases or inflammation, have not been identified. Experimental Approach: We developed a homology modelling for VISTA 3D structure and subsequent virtual screening for low MW ligands binding to VISTA. Visualization of the binding postures of docked ligands with protein VISTA indicated that compound M351-0056 targeted VISTA. The biological activities of compound M351-0056 targeting VISTA were investigated in vitro using monocytes and T cells and in vivo, using mice with imiquimod-induced dermatitis. Key Results: The KD value of M351-0056 for human VISTA-extracellular domain was 12.60 ± 3.84 μM as assessed by microscale thermophoresis. M351-0056 decreased cytokine secretion from PBMCs or human CD4+ T cells, suppressed proliferation of PBMCs and enhanced expression of Foxp3+ T cells. These effects of M351-0056 modulating VISTA involved the JAK2–STAT2 pathway. Daily administration of M351-0056 ameliorated imiquimod-induced psoriasis-like dermatitis. Expression of mRNA and protein of inflammatory cytokines in psoriatic lesions was decreased after M351-0056 treatment. Conclusion and Implications: The compound M351-0056 showed high affinity for VISTA and may modulate its immune function in vitro and in vivo. Our finding provides a lead compound for therapeutically enhancing VISTA-mediated pathways to benefit the treatment of autoimmune diseases or inflammation.