Venetoclax-induced degradation of VP8* lectin domain disrupts group A rotavirus replication

Group A Rotavirus (RVA) poses a significant health risk. Unfortunately, there are currently no the Food and Drug Administration (FDA) approved antiviral compounds available for treating RVA-induced diarrhea. The lectin-like domain of VP8* plays an important role in the RVA lifecycle. In this study, to identify potential anti-RVA drugs, the Computer-aided drug design (CADD) was used to conduct virtual screening targeting the VP8* lectin-like domain, utilizing the FDA compound library. Seven candidate compounds that inhibited RVA infection were identified, among which Venetoclax exhibited optimal inhibitory effects on RVA with inhibition of >90 %. Venetoclax reduces RVA replication in a dose-dependent manner (IC₅₀ = 1.26 μM) without cytotoxicity (CC₅₀ = 56.83 μM). It possesses the ability to reduce viral titers and inhibit viral structural protein expression. Time-of-addition assays suggest that the compound interferes with the attachment, internalization, and replication stages of the viral infection cycle. Additionally, Venetoclax degrades the VP8* lectin-like domain via the lysosomal pathway, thereby inhibiting RVA infection. The antiviral efficacy of Venetoclax was further confirmed in suckling mouse model, where treatment alleviated RVA-induced diarrhea. These findings demonstrate that Venetoclax effectively inhibits RVA infection both in vitro and in vivo, highlighting its potential as a therapeutic candidate against RVA.