Antiviral strategies against human norovirus: Molecular targets, therapeutics, and vaccine development

Human norovirus (HuNoV) is a leading cause of acute viral gastroenteritis worldwide and represents a major unmet challenge in antiviral drug and vaccine development. HuNoV is a non-enveloped, positive-sense RNA virus characterized by extensive genetic diversity and rapid evolution, which contribute to recurrent outbreaks in the absence of effective licensed therapeutics. Despite substantial progress in understanding HuNoV molecular biology, effective antiviral strategies remain limited, in part due to historical limitations in experimental model systems and the virus's ability to evade host antiviral responses. Recent advances in HuNoV in vitro culture systems, particularly human intestinal enteroids, and inhibitor screening platforms have improved the identification of antiviral candidates, while parallel efforts in vaccine development have yielded immunogenicity data in preclinical and early-stage clinical studies. However, significant challenges persist, including antigenic diversity, strain-specific immunity, and limited correlates of protection. This review provides a critical analysis of the molecular mechanisms governing HuNoV infection, immune evasion, and replication, with a focused emphasis on key antiviral targets, inhibitory strategies, and therapeutic development. Moreover, this review outlines key limitations and future directions for the development of effective therapeutic and preventive measures against HuNoV infection.