Repositioning baloxavir marboxil as VISTA agonist that ameliorates experimental asthma

作者：Jian-wen Di, Yixin Wang, Ruixue Ma, Zhijie Luo, Wenting Chen, Wanmei Liu, Dingyi Yuan, Yuying Zhang, Yin-hao Wu, Caiping Chen, Jun Liu · 发表于：Cell Biology and Toxicology · 年份：2024 · DOI：10.1007/s10565-024-09852-x · 被引用次数：7 · 研究领域：Immune Cell Function and Interaction、IL-33, ST2, and ILC Pathways、Asthma and respiratory diseases

Abstract V-type immunoglobulin domain–containing suppressor of T-cell activation (VISTA), a novel negative checkpoint regulator, plays an essential role in allergic pulmonary inflammation in mice. Treatment with a VISTA agonistic antibody could significantly improve asthma symptoms. Thus, for allergic asthma treatment, VISTA targeting may be a compelling approach. In this study, we examined the functional mechanism of VISTA in allergic pulmonary inflammation and screened the FDA-approved drugs for VISTA agonists. By using mass cytometry (CyTOF), we found that VISTA deficiency primarily increased lung macrophage infiltration in the OVA-induced asthma model, accompanied by an increased proportion of M1 macrophages (CD11b + F4/80 + CD86 + ) and a decreased proportion of M2 macrophages (CD11b + F4/80 + CD206 + ). Further in vitro studies showed that VISTA deficiency promoted M1 polarization and inhibited M2 polarization of bone marrow–derived macrophages (BMDMs). Importantly, we discovered baloxavir marboxil (BXM) as a VISTA agonist by virtual screening of FDA-approved drugs. The surface plasmon resonance (SPR) assays revealed that BXM (KD = 1.07 µM) as well as its active form, baloxavir acid (BXA) (KD = 0.21 µM), could directly bind to VISTA with high affinity. Notably, treatment with BXM significantly ameliorated asthma symptoms, including less lung inflammation, mucus secretion, and the generation of Th2 cytokines (IL-5, IL-13, and IL-4), which were dramatically attenuated by ...