Discovery of vina-ginsenoside R18 as a novel dual-target inhibitor of dengue virus envelope protein and RNA-dependent RNA polymerase

Dengue virus (DENV) poses a serious health threat globally for which specific antivirals are not available. Envelope (E) protein and RNA-dependent RNA polymerase (RdRp) from DENV represent the most critical targets for the development of antivirals that inhibit viral adsorption for entry and genome replication, respectively; no dual inhibitors targeting E/RdRp have been reported to date. Vina-ginsenoside R18 (R18), a triterpenoid saponin isolated from Panax notoginseng , was shown to target E protein domain III to inhibit binding of E protein to integrin beta3, thus preventing viral adsorption to the host surface receptor. R18 selectively targets RdRp protein and induces a conformational change, leading to a decrease in enzyme activity. Consequently, R18 represses DENV infection by acting at viral binding, entry, and replication stages, and attenuates the pathologic symptoms of DENV-infected ICR suckling and AG129 mice. These results showed R18 to be a novel dual E/RdRp inhibitor that can serve a potential agent against DENV infection.