Noroviruses are the major cause of non-bacterial gastroenteritis and no direct treatment or vaccines currently exist. To characterize their natural receptor determinants, we applied nuclear magnetic resonance (NMR) techniques to investigate the recognition of histo-blood group antigens. These terminal carbohydrate structures on glycoproteins or -lipids serve as attachment factors or receptors for the virus to enter the host cells. Following the resulting description of the interaction at atomic resolution we identified a conserved sub-pocket that was then the target of NMR screening. Low molecular weight binders of the receptor recognition site of virus-like particles of the GII.4 Norovirus Ast6139 were identified. On the basis of these NMR experiments a heterobifunctional ligand was then designed and forms the basis for highly potent, multivalent entry inhibitors. The benefits of using entire virus-like particles for the investigation of the receptor specificity and their application towards the rational design of entry inhibitors are discussed.

Development of multivalent entry inhibitors of Norovirus infections from fragment-based screening

243rd National Meeting (2012)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.