2--c-methylcytidine and Body-Weight

Human noroviruses are a major cause of food-borne illness, accountable for 50% of all-etiologies outbreaks of acute gastroenteritis (in both developing and developed countries). There is no vaccine or antiviral drug for the prophylaxis or treatment of norovirus-induced gastroenteritis. We recently reported the inhibitory effect of 2'-C-methylcytidine (2CMC), a hepatitis C virus polymerase inhibitor, on the in vitro replication of murine norovirus (MNV). Here we evaluated the inhibitory effect of 2CMC on in vitro human norovirus replication through a Norwalk virus replicon model and in a mouse model by using AG129 mice orally infected with MNV. Survival, weight, and fecal consistency were monitored, and viral loads in stool samples and organs were quantified. Intestines were examined histologically. 2CMC reduced Norwalk virus replicon replication in a dose-dependent manner and was able to clear cells of the replicon. Treatment of MNV-infected AG129 mice with 2CMC (i) prevented norovirus-induced diarrhea; (ii) markedly delayed the appearance of viral RNA and reduced viral RNA titers in the intestine, mesenteric lymph nodes, spleen, lungs, and stool; (iii) completely prevented virus-induced mortality; and (iv) resulted in protective immunity against a rechallenge. We demonstrate for the first time that a small-molecule inhibitor of norovirus replication protects from virus-induced disease and mortality in a relevant animal model. These findings pave the way for the development of potent and safe antivirals as prophylaxis and therapy of norovirus infection.

Topics: Animal Structures; Animals; Antiviral Agents; Body Weight; Caliciviridae Infections; Cytidine; Diarrhea; Disease Models, Animal; Feces; Female; Male; Mice; Norovirus; Norwalk virus; RNA, Viral; Survival Analysis; Viral Load; Virus Replication

Yellow fever virus (YFV) continues to cause outbreaks of disease in endemic areas where vaccine is underutilized. Due to the effectiveness of the vaccine, antiviral development solely for the treatment of YFV is not feasible, but antivirals that are effective in the treatment of related viral diseases may be characterized for potential use against YFV as a secondary indication disease. 2'-C-methylcytidine (2'-C-MeC), a compound active against hepatitis C virus, was found to have activity against the 17D vaccine strain of YFV in cell culture (EC(90)=0.32 microg/ml, SI=141). This compound was effective when added as late as 16 h after virus challenge of Vero cells. When administered to YFV-infected hamsters 4 h prior to virus challenge at a dose as low as 80 mg/kg/d, 2'-C-MeC was effective in significantly improving survival and other disease parameters (weight change, serum ALT, and liver virus titers). Disease was improved when compound was administered beginning as late as 3 d post-virus infection. Broadly active antiviral compounds, such as 2'-C-MeC, represent potential for the development of compounds active against related viruses for the treatment of YFV.

Topics: Alanine Transaminase; Animals; Antiviral Agents; Aspartate Aminotransferases; Body Weight; Chlorocebus aethiops; Cricetinae; Cytidine; Female; Liver; Mesocricetus; Survival Analysis; Treatment Outcome; Vero Cells; Viral Load; Yellow Fever; Yellow fever virus