Library Screen for Inhibitors Targeting Norovirus Binding to Histo-Blood Group Antigen Receptors

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Abstract
Human noroviruses (NVs) are a common cause of nonbacterial gastroenteritis. The disease is difficult to control due to its widespread nature and the lack of antivirals or vaccines against NVs. The recent identification of human histo-blood group antigens (HBGAs) as NV receptors opens a new way for the discovery and design of antivirals against NVs. A saliva-based enzyme immune assay (EIA) was used to screen a synthetic-compound library for inhibition of the binding of norovirus-like particles to HBGA receptors. Among 5,000 compounds tested in the first round of screening, 153 compounds exhibited >50% inhibition of the binding of VA387 (an NV that binds to A, B, and H epitopes) to the A antigen in saliva at ∼50 μg/ml, and 14 of the 153 compounds revealed strong inhibition, with a 50% effective concentration of <15 μM. Ten and 11 of the 14 compounds also revealed inhibition of the binding of VA387 to the B and H antigens, respectively. Seven and 6 of the 14 compounds also blocked the binding of the prototype Norwalk virus (A and H binder) to the A and H antigens, respectively. One compound significantly inhibited the binding of MOH (A and B binder) to the A and B antigens, but no compound revealed any inhibitory effect on the binding of a Lewis binding strain (VA207) to the Lewis antigens. The EIA is a high-throughput method for large-scale library screening for antivirals against NVs. Studies to further characterize the lead compounds and to screen additional compounds for other NVs are ongoing in our laboratory.