HSP90 inhibitor NVP-HSP990 alleviates rotavirus infection

Rotavirus (RV) infection is a significant cause of hospitalization and mortality in infants and young children. Although conventional symptomatic treatments usually appear effective, tens of thousands of infants and young children still die each year due to the absence of safe and effective anti-RV drugs. Heat shock protein 90 (HSP90) is usually required for efficient viral infection; however, due to unsatisfactory antiviral efficacy and toxicity, there has been no HSP90-targeting agents applied for clinical antiviral therapy currently. Here, we demonstrated that NVP-HSP990, a novel small-molecule HSP90 inhibitor with excellent oral bioavailability and brain penetration, was a potent inhibitor of RV infection with much bigger selectivity index (SI) than traditional HSP990 inhibitors. NVP-HSP990 potently inhibited RV replication in vitro without blocking infection establishment. NVP-HSP990 remarkably restored gene expressions of most KEGG pathways disturbed by RV infection in intestinal cells, except some inflammatory pathways (IL-17, TNF, etc.). To be noted, NVP-HSP990 significantly altered gene expressions in MAPK signaling pathway and inhibited RV-induced activation of MAPK as well as disruption of tight junctions in Caco-2 cells. More importantly, NVP-HSP990 effectively alleviated RV diarrhea, competently inhibited RV replication, and obviously prevented pathological lesions of intestine in BALB/c suckling mice. Therefore, our results suggested that NVP-HSP990 can be a promising antiviral drug candidate against RV infection.