2--c-methylcytidine and Gastroenteritis

Noroviruses are members of the family Caliciviridae. Norovirus infections are a global health burden that impacts >20 million individuals annually in the U.S. alone. Noroviruses are associated with high morbidity among vulnerable populations, particularly immunocompromised patients. This perspective highlights recent developments related to the discovery and development of norovirus-specific small-molecule therapeutics as well as recent advances in our understanding of norovirus biology and pathogenesis. Most of the work in this area is at the early discovery stage and has been primarily focused on inhibitors of norovirus 3C-like protease and RNA dependent RNA polymerase. However, recent discoveries emanating from basic studies in norovirus research have resulted in the identification of new host-related drug targets that can be exploited. A repurposed compound has been advanced to human clinical studies.

Topics: Animals; Antiviral Agents; Caliciviridae Infections; Cysteine Proteinase Inhibitors; Gastroenteritis; Genes, Viral; Humans; Norovirus; RNA-Dependent RNA Polymerase; Virus Internalization

Prolonged norovirus shedding may occur in certain patients, such as organ transplant recipients. We established a mouse model for persistent norovirus infection (using the mouse norovirus MNV.CR6 strain). The nucleoside viral polymerase inhibitor 2'-C-methylcytidine (2CMC), but not favipiravir (T-705), reduced viral shedding to undetectable levels. Viral rebound was observed after stopping treatment, which was again effectively controlled by treatment with 2CMC. No drug-resistant variants emerged.

Topics: Amides; Animals; Caliciviridae Infections; Cytidine; Disease Models, Animal; Feces; Gastroenteritis; Mice; Mice, Knockout; Norovirus; Pyrazines; Receptors, Interferon; Transplant Recipients; Virus Shedding