Norovirus infections affect more than 200 million people worldwide every year. Since these viruses are highly contagious and cause epidemic outbreaks norovirus infections constitute a massive economic burden. Currently there are neither vaccination strategies nor therapeutics to cure the infection. We have designed first prototype entry-inhibitors against norovirus infections employing a rational approach based on NMR binding studies with virus like particles (VLPs). In order to develop these prototype inhibitors into potent antivirals information is needed on the thermodynamics and kinetics of binding of entry-inhibitors to the viral coat protein VP1. Binding data will be related to binding topologies on the surface of VP1. We suggest protein NMR experiments with selectively 2H/15N/13C amino acid labeled VP1 to study the relative binding topologies of natural attachment factors and entry-inhibitors. Isothermal titration calorimetry (ITC) and surface plasmon resonance (SPR) will yield enthalpies and entropies of binding as well as kinetic data on the binding process. Thermodynamic data in combination with relative binding topologies will then deliver guides for the rational modification of the first generation inhibitors to obtain better affinities. The modified compounds will be subjected to the same set of experiments, and depending on the results the optimization process proceeds in an iterative manner until potent entry-inhibitors are identified. Since VP1 is expressed as a homodimer (P-dimer), potent inhibitor candidates will be linked to a polymeric backbone as described earlier in order to achieve better avidity. Finally, we hope to come up with a first rationally designed entry-inhibitor against norovirus infections.