Human norovirus is the dominating+ cause of outbreaks of viral gastroenteritis across all age groups, with an estimated 684 million cases worldwide and 219,000 deaths per year. Outbreaks of human norovirus frequently occur in enclosed settings (e.g. cruise ships, hospitals, nursing homes). This is economically relevant, as it is estimated to cost 4.2 billion USD in direct health system and 60.3 billion USD in social costs. Although symptoms are self-limited to two to three days, the illness can be severe in young children, elderly, or immunocompromised people. The complete lack of treatment or vaccination limits counter measurements to easing symptoms. Additionally, spreading is limited by preventative measures, such as isolating infected individuals. An adequate treatment for patients as well as a possible early treatment (before symptoms appear) for people in the near environment of a beginning outbreak, including nurses and other staff, could prevent outbreaks from spreading. Therefore, inexpensive treatments with a minimum of side effects that can be delivered to patients and people in their surrounding are urgently needed. For more than four decades, antiviral research was hampered by the lack of cell culture systems for human norovirus propagation. Therefore, surrogate systems, such as murine norovirus and feline calicivirus, were used. Human noroviruses typically require histo-blood group antigens (HBGAs) as co-factors for viral infection. Thus, the HBGA pocket is the main target region on the viral capsid for the development of antivirals. In this thesis, a panel of synthetic antivirals and natural extracts, including a set of 31 different honeys, were screened using various techniques (X-ray crystallography, ELISA, DLS, and EM) to identify potential norovirus capsid inhibitors. Several Nanobodies (Fab fragments of camelid derived heavy chain only antibodies) directed specifically against genotype GI.1 of human norovirus inhibited virus like particles (VLPs) in surrogate attachment inhibition ELISAs. However, inhibition by these Nanobodies was specifically directed against their respective genotype and showed limited cross-reactivity. The high specificity of the Nanobodies limits their use as broadly reactive antivirals. Of the Natural extracts, date syrup, wine, barley malt, coconut blossom syrup, apple sweetener, different types of honey and propolis inhibited the binding of VLPs to HBGAs. Treatment of VLPs with these compounds resulted in the disruption of VLP integrity and particle aggregation. Most natural extracts showed broad reactivity against VLPs of several genotypes. Preliminary structural analysis revealed the presence of small, unidentified ligand(s) for date syrup, coconut blossom syrup, apple sweetener, and honey. The strongest inhibition was observed with date syrup, wine, and propolis. Three flavonols, common to these natural extracts, were identified as inhibiting compounds. To address if a combinatorial approach could improve the performance of the individual inhibitors, special combinatorial ELISAs were designed to assess the interaction between two inhibitors. These assays revealed combinations of Nanobodies with the HMO 2’FL or natural extracts to have additive or synergistic inhibition. This demonstrated a combinatorial approach with natural extracts and Nanobodies could be a comparatively easy, safe, and affordable treatment that could be administered to people suffering from norovirus disease and healthy people in the surrounding of a beginning outbreak.