The genus Orthoflavivirus encompasses multiple mosquito-borne human pathogens—dengue virus (DENV; four serotypes), Zika virus (ZIKV), West Nile virus (WNV), Japanese encephalitis virus (JEV), tick-borne encephalitis virus (TBEV), and yellow fever virus (YFV)—that together threaten over half of the global population. These viruses encode seven nonstructural proteins in their genome, including NS1, a secreted glycoprotein that acts as a viral toxin by disrupting endothelial integrity and promoting vascular leak. Flavivirus NS1 harbors two conserved N-glycosylation sites (N130 and N207), with a third site (N175) present in WNV and JEV. Given the conservation and functional importance of these glycan sites, we hypothesized that lectins targeting high-mannose N-glycans (HMG) could act as broadly effective antivirals against orthoflaviviruses. We focused on two lectins: Oscillatoria agardhii agglutinin (OAA), which has two HMG binding sites, and Burkholderia oklahomensis agglutinin (BOA), which has four. Biolayer interferometry revealed mid-nM affinity of OAA and low-nM affinity of BOA for DENV NS1, with similar binding across other flavivirus NS1s. To further understand this interaction, we employed glycan profiling by LC-MS and size exclusion chromatography. Ongoing cryo-EM studies aim to resolve the OAA-NS1 complex. Functionally, both OAA and BOA inhibit vascular leak and hinder flavivirus infection both in vitro and in vivo. These findings demonstrate that OAA and BOA potently bind conserved glycans on NS1 and block flavivirus pathology, supporting glycan-targeting lectins as a promising class of pan-orthoflavivirus therapeutics.
Hall et al. (Sun,) studied this question.