The pan-African natural products library compounds oleanolic acid, poinsettifolin B, and rhuschalcone III disrupt SARS-CoV-2 spike-host ACE2 interactions and SARS-CoV-2 replication.

Natural product (NP)-based chemical libraries are a rich source of antiviral compounds that can serve as the basis for new therapeutic leads to treat viral diseases, particularly for individuals lacking sustained access to existing vaccines and therapeutics. To identify new NP-based candidate inhibitors of SARS-CoV-2 cellular entry and viral replication, we screened the pan-African Natural Products Library (p-ANAPL), a collection of physical pure compounds obtained from African medicinal plants, for NPs that can disrupt the in vitro interaction of the SARS-CoV-2 Spike receptor-binding domain (RBD) with its host ACE2 entry receptor. This screen identified three compounds - oleanolic acid, poinsettifolin B, and rhuschalcone III - which disrupt RBD/ACE2 interactions with half-maximal inhibitory concentrations (IC50s) of 0.5-2.4 µM but do not disrupt an unrelated PD-1/PD-L1 host ligand/receptor binding pair. Oleanolic acid and rhuschalcone III, but not poinsettifolin B, additionally inhibited SARS-CoV-2 replication in Vero cells without cytotoxicity at low micromolar concentrations. Computational modelling indicated that all three compounds interact with numerous RBD and ACE2 residues, including a subset conserved across SARS-CoV-2 variants of concern. Taken together, we identify three NPs that selectively interfere with factors involved in SARS-CoV-2 entry and/or viral replication, representing new antiviral leads for COVID-19 management in resource-limited areas.