HSP90 inhibitor NVP-HSP990 alleviates rotavirus infection

Abstract

AbstractRotavirus (RV) infection is an important cause of hospitalization and even death of infants and young children, but conventional antiviral drugs such as nucleoside analogues as well as type I interferon are usually not included in treatment of RV diarrhea due to adverse side effects. Host heat shock protein 90 (HSP90) is commonly up-regulated and exploited by a series of viruses for successful infection including RV, rendering the possibility of small molecule HSP90 inhibitors as novel antiviral agents for control of RV infection. Here, we tested the effect of a novel HSP90 inhibitor NVP-HSP990 (HSP990), which possesses excellent oral bioavailability, on alleviating RV infectionin vitroandin vivo. We found that HSP990 was low-cytotoxic and potently inhibited RV replication in MA104 and Caco-2 cells, though largely did not influence initial establishment of RV infection. Meanwhile, HSP990 also remarkably inhibited the activation of MAPK pathways induced by RV infection. HSP990 effectively alleviates RV diarrhea of BABL/c suckling mice, and remarkably inhibited RV replication as well as expressions of pro-inflammatory cytokines/chemokines in epithelial cells of intestinal mucosa.IMPORTANCEWe revealed the novel HSP90 small molecule inhibitor HSP990 was a novel potent antiviral agent with low cytotoxity for the first time. HSP990 significantly inhibited RV replicationin vitroandin vivowith low cytotoxicity and effectively alleviated RV diarrhea. These findings indicated that HSP990 could be a novel promising candidate of antiviral drug for RV infection.