Inhibition of norovirus replication by the nucleoside analogue 2'-C-methylcytidine.
We here report on the activity of 2'-C-methylcytidine (2CMC) [a nucleoside polymerase inhibitor of the hepatitis C virus (HCV)] on the in vitro replication of (murine) norovirus (MNV). 2CMC inhibits (i) virus-induced CPE formation, (ii) viral RNA synthesis and (iii) infectious progeny formation with EC(50) values of ∼2μM. 2CMC acts at a time-point that coincides with the onset of viral RNA synthesis. Even following 30 passages of selective pressure no MNV-resistant virus was selected, which is in line with the high barrier to resistance of the nucleoside analogue for HCV. When combined with the broad-spectrum RNA virus inhibitor ribavirin, a marked antagonistic activity was observed indicating that these molecules should not be combined for the treatment of norovirus infections. Our results suggest that 2'-C-methyl nucleoside analogues should be further explored for the treatment and prophylaxis of norovirus infections.
Laboratório de Microbiologia, Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, Rua de Jorge Viterbo Ferreira no. 228, 4050-313 Porto, Portugal.
J
J
Rocha-Pereira
D
D
Jochmans
K
K
Dallmeier
P
P
Leyssen
R
R
Cunha
I
I
Costa
M S J
MS
Nascimento
J
J
Neyts
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D002460:Cell Line; D003562:Cytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D024882:Drug Resistance, Viral / Q000235:genetics; D051379:Mice; D029322:Norovirus / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D012254:Ribavirin / Q000494:pharmacology; D014779:Virus Replication / Q000187:drug effects*
D000998:Antiviral Agents; C513402:2'-C-methylcytidine; D012254:Ribavirin; D003562:Cytidine