RT Journal Article SR Electronic T1 Chelerythrine as an anti-Zika virus agent: therapeutic potential and mode of action JF bioRxiv FD Cold Spring Harbor Laboratory SP 2022.12.16.520682 DO 10.1101/2022.12.16.520682 A1 Erica EspaƱo A1 Jiyeon Kim A1 Chong-Kil Lee A1 Robert G. Webster A1 Richard J. Webby A1 Jeong-Ki Kim YR 2022 UL http://biorxiv.org/content/early/2022/12/19/2022.12.16.520682.abstract AB Zika virus (ZIKV) is a mosquito-borne virus that has been associated with adult and neonatal neurological conditions. So far, there is no approved drug or vaccine against ZIKV infection; thus, ZIKV remains a global health threat. Here, we explored the effects of chelerythrine (CTC), a known protein kinase C (PKC) inhibitor, against ZIKV infection in cell culture models to determine its potential as a therapeutic agent for ZIKV infection. We found that CTC protected Vero cells from ZIKV-induced cytopathic effects in a dose-dependent manner. It also reduced the production of ZIKV in Vero and A549 cells. In contrast, other PKC inhibitors failed to protect Vero cells from ZIKV-induced cytopathic effects, indicating PKC-independent mechanisms underlying the effects of CTC on ZIKV. Further investigation suggested that CTC inhibited ZIKV attachment/binding rather than internalization in the host cells. Pretreatment of cell-free ZIKV particles rather than pretreatment of cells with CTC resulted in reduced ZIKV infectivity in vitro, indicating that CTC blocked the attachment/binding of the ZIKV particles to host factors. In silico analyses suggested that these effects are potentially due to the binding of CTC to the ZIKV E protein, which may occlude the interaction of the E protein with attachment factors or receptors on the host cell surface. Overall, our findings suggest that CTC reduces the infectivity of ZIKV particles through PKC- and cell-independent mechanisms. Our findings also support further exploration of CTC as an anti-ZIKV agent.Competing Interest StatementThe authors have declared no competing interest.