Identification of (20R)-protopanaxadiol from Panax ginseng as a novel anti-SARS-CoV-2 compound.

COVID-19 remains a global health concern, yet current antivirals are restricted to high-risk patients and face issues of resistance. To establish a safer evaluation system, we constructed a noninfectious SARS-CoV-2 replicon using a BAC vector driven by the CMV promoter. Among the tested cell lines, HuH-7.6c supported the most efficient replication. Replication was inhibited by remdesivir, nirmatrelvir, and molnupiravir, but not by favipiravir or AT-527. A screening of 373 food-derived compounds identified (20R)-protopanaxadiol (PPD), a ginseng metabolite, as a novel inhibitor. Together, this work highlights this BAC-vectored replicon as a practical platform for antiviral screening and identifies the potential of safe, food-derived supplements in combating SARS-CoV-2.