Time-dependent processing of dengue virus polyprotein yields multiple capsid forms that disrupt cellular homeostasis

Dengue virus infections spread to new geographical regions every year, cause significant morbidity and mortality, yet the progress in drug/vaccine development is limited due to an incomplete understanding of its life cycle. While a few of the proteins coded by this virus exist in multiple forms, the sequential events of polyprotein processing to yield them and the consequential effects on host cells are unclear. In this study, the virus infected cell culture data suggest that the polyprotein undergoes a time-dependent processing to yield multiple capsid forms, ie, capsid, capsid-anchor, capsid-anchor-pr, capsid-anchor-prM. Among them, the c-anc and c-anc-pr were found to localize to the mitochondria upon transfection into the HEK cells. The transmission electron microscopy studies suggest that c-anc induces mitochondrial fragmentation. Further studies showed that c-anc affects the mitochondrial fusion-related proteins and the genes involved in their functions. The pulldown experiments indicate that c-anc also interacts with 1-syntrophin (SNTA1), a cytoplasmic protein that plays a role in redox potential, oxidative stress and mitochondrial biogenesis. Importantly, the mitostress analyses suggest that c-anc triggers impaired mitochondrial dysfunctions like potential, respiration and ATP generation. In this study, we also identify ursonic acid (UNA) as a c-anc binding compound that restores mitochondrial functions and suppresses virus multiplication in vitro, ex vivo and in mice. The revealed disrupted mitochondrial homeostasis appears to be common to DENV, ZIKV, JEV, YFV, HCV, ASFV and SARS-CoV-2; hence, UNA or its related compounds could be considered as inhibitors for the above virus infections.