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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 \u2013 oleanolic acid, poinsettifolin B, and rhuschalcone III \u2013 which disrupt RBD\/ACE2 interactions with half-maximal inhibitory concentrations (IC\n                    <jats:sub>50<\/jats:sub>\n                    s) of 0.5\u20132.4 \u00b5M 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.\n                  <\/jats:p>","DOI":"10.1186\/s40360-026-01264-3","type":"journal-article","created":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T20:14:57Z","timestamp":1792613697000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["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"],"prefix":"10.1186","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-0615-0335","authenticated-orcid":false,"given":"Mathieu J. 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