Novel Antiviral Compound Discovery Targeting Lassa Virus Nucleoprotein Endonuclease Activity Using Nigerian Medicinal Plant Libraries

The nucleoprotein (NP) endonuclease domain of Lassa mammarenavirus plays an indispensable role in viral replication by degrading host antiviral RNA, making it an attractive antiviral drug target for which no approved inhibitor yet exists. Nigeria's vast medicinal plant biodiversity, largely unexplored through modern drug discovery pipelines, represents a potential source of novel antiviral lead compounds. This study conducts a systematic discovery programme targeting Lassa NP endonuclease activity using fractionated extracts from 50 Nigerian medicinal plants with ethnopharmacological relevance to fever and haemorrhagic conditions. Medicinal plants will be collected across six geopolitical zones in consultation with herbalists and the Natural Products Research Institute, Nsukka. Extracts will be fractionated by solid-phase extraction, and fractions subjected to high-throughput fluorescence-based endonuclease inhibition assays. Active fractions will undergo bioassay-guided fractionation and LC-MS/MS dereplication to identify bioactive compounds. Lead compounds will be tested in BSL-3 cell-based Lassa virus inhibition assays (VERO cells), and selectivity indices calculated. Molecular docking simulations (AutoDock Vina) will characterise binding modes in the NP endonuclease active site. Hits will undergo preliminary toxicity assessment using zebrafish embryo models. This research develops an original Nigerian medicinal plant-to-antiviral lead pipeline, making a novel theoretical contribution at the interface of ethnopharmacology, structural virology, and drug discovery while addressing a critical unmet therapeutic need for Lassa fever. Keywords: Lassa virus, nucleoprotein endonuclease, antiviral discovery, Nigerian medicinal plants, drug target