In vitro selected Con1 subgenomic replicons resistant to 2'-C-methyl-cytidine or to R1479 show lack of cross resistance.
The HCV polymerase is an attractive target for the development of new and specific anti-HCV drugs. Herein, the characterization of the inhibitory effect of 2'-C-Methyl-Cytidine shows that it is a potent inhibitor of both genotype 1b and 1a HCV replicon replication, both of laboratory-optimized as well as of NS5B clinical isolates-chimera replicons. The corresponding 5'-triphosphate derivative is a potent inhibitor of native HCV replicase isolated from replicon cells and of the recombinant genotype 1b and 1a HCV polymerase-mediated RNA synthesis. Resistance to 2'-C-Methyl-Cytidine was mapped to amino acid substitution S282T in the NS5B coding region. Cross-resistance was observed to 2'-C-Methyl-Adenosine but not to interferon alpha-2a, to non-nucleoside HCV polymerase inhibitors or to R1479, a new and potent nucleoside inhibitor of NS5B polymerase. In vitro studies mapped resistance to R1479 to amino acid substitutions S96T and S96T/N142T of the NS5B polymerase. These mutations did not confer resistance to 2-C-Methyl-Cytidine, thus confirming the lack of cross-resistance between these two HCV inhibitors. These data will allow the optimization of new polymerase inhibitors and their use in combination therapy.
Le Pogam
Sophie
S
Roche Palo Alto LLC, S3-1, 3431 Hillview Avenue, Palo Alto, CA 94304, USA.
Jiang
Wen-Rong
WR
Leveque
Vincent
V
Rajyaguru
Sonal
S
Ma
Han
H
Kang
Hyunsoon
H
Jiang
Sharon
S
Singer
Margaret
M
Ali
Samir
S
Klumpp
Klaus
K
Smith
Dave
D
Symons
Julian
J
Cammack
Nick
N
Nájera
Isabel
I
D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D003562:Cytidine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D024882:Drug Resistance, Viral; D016679:Genome, Viral; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology; D015394:Molecular Structure; D012367:RNA, Viral; D014779:Virus Replication / Q000187:drug effects
D000998:Antiviral Agents; D016898:Interferon-alpha; D012367:RNA, Viral; C513402:2'-C-methylcytidine; D003562:Cytidine; C508950:4'-azidocytidine