The Viral Polymerase Inhibitor 2 '-C-Methylcytidine Inhibits Norwalk Virus Replication and Protects against Norovirus-Induced Diarrhea and Mortality in a Mouse Model

• Type: Article in International Scientific Journal
• Date: 2013

Authors

Joana Rocha Pereira (Author) Other; Dirk Jochmans (Author) Other; Yannick Debing (Author) Other; Erik Verbeken (Author) Other; Maria S J Nascimento (Author) FFUP; Johan Neyts (Author) Other

Journal

Title: Journal of Virology

Vol. 87

Pages: 11798-11805

ISSN: 0022-538X

Publisher: American Society for Microbiology

Indexing

ISI Web of Knowledge - 53 Citations

Scopus - 29 Citations

Scientific classification

FOS: Natural sciences > Biological sciences

Other information

Authenticus ID: P-006-6AF

DOI: 10.1128/jvi.02064-13

Abstract (EN): 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 norovirusinduced 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.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 8