Vibsanin B Targets HSP90? To Inhibit Interstitial Leukocyte Migration And Ameliorates Experimental Autoimmune Encephalomyelitis

Objective: Inflammation associated disease is still a big threat for human health.Interstitial leukocyte migration plays a critical role in inflammation and offers a therapeutic target for treating inflammation associated diseases such as multiple sclerosis(MS).Identifying small molecular compounds for inhibiting unwanted leukocyte migration provides promise for the treatment of the disorders.In the history of drug development,a large proportion of drugs are derived from natural products or their derivatives.Thus,natural product as a naturally occurring chemical structure takes an important part in drug discovery and development.The objective of this study is to obtain bioactive natural products that are isolated from plants for inhibiting leukocyte migration,elucidate the molecular mechanism of action and evaluate their clinical implication in inflammation associated diseases such as multiple sclerosis.Method: In this study,we used the following methods: 1.Under fluorescent microscope,we lively and dynamically observed the leukocyte migration behaviour in transgenic zebrafish(Tg:zlyz-EGFP)embryos at 3dpf at whole animal level.Using this screening assay,we screened the natural product library for obtaining bioactive natural products to inhibit leukocyte migration.2.Using activity-based protein profile technology,we ?fished? the direct target of the bioactive natural product.Then,using gene knockdown and molecular biology technology,we validated the relationship between the direct target of Vibsanin B and its bioactivity,thus elucidating its molecular mechanism.3.Using the animal model mice Experimental autoimmune encephalomyelitis(EAE)for multiple sclerosis,we evaluated the clinical implication of the bioactive natural product for treating inflammation associated diseases.Result: 1.We screened a natural product Vibsanin B that can inhibit zebrafish leukocyte migration and human THP-1 cell chemotaxis;2.Vibsanin B directly and selectively targets HSP90? carboxy-terminal domain(CTD)and inhibits HSP90? chaperone activity in vitro.Additionally,HSP90 inactivation leads to decreased zebrafish leukocyte inflammatory migration,which is consistent with the biological consequence of Vibsanin B for inhibiting leukocyte migration;.3.To some extent,Vibsanin B can induce decreased leukocyte infiltration into central nervous system(CNS)and ameliorate mice EAE severity.Conclusion: In summary,Vibsanin B is a novel HSP90? isoform specific inhibitor that inhibits interstitial leukocyte migration and provides a promising drug lead for the treatment of inflammation associated diseases.