The mechanism of action of beta-D-2'-deoxy-2'-fluoro-2'-C-methylcytidine involves a second metabolic pathway leading to beta-D-2'-deoxy-2'-fluoro-2'-C-methyluridine 5'-triphosphate, a potent inhibitor of the hepatitis C virus RNA-dependent RNA polymerase.
beta-D-2'-Deoxy-2'-fluoro-2'-C-methylcytidine (PSI-6130) is a potent inhibitor of hepatitis C virus (HCV) RNA replication in an HCV replicon assay. The 5'-triphosphate of PSI-6130 is a competitive inhibitor of the HCV RNA-dependent RNA polymerase (RdRp) and acts as a nonobligate chain terminator. Recently, it has been shown that the metabolism of PSI-6130 also results in the formation of the 5'-triphosphate of the uridine congener, beta-D-2'-deoxy-2'-fluoro-2'-C-methyluridine (PSI-6206; RO2433). Here we show that the formation of the 5'-triphosphate of RO2433 (RO2433-TP) requires the deamination of PSI-6130 monophosphate and that RO2433 monophosphate is subsequently phosphorylated to the corresponding di- and triphosphates by cellular UMP-CMP kinase and nucleoside diphosphate kinase, respectively. RO2433-TP is a potent inhibitor of the HCV RdRp; however, both enzymatic and cell-based assays show that PSI-6130 triphosphate is a more potent inhibitor of the HCV RdRp than RO2433-TP.
Murakami
Eisuke
E
Pharmasset, Inc., 303 A College Road East, Princeton, NJ 08540, USA.
Niu
Congrong
C
Bao
Haiying
H
Micolochick Steuer
Holly M
HM
Whitaker
Tony
T
Nachman
Tammy
T
Sofia
Michael A
MA
Wang
Peiyuan
P
Otto
Michael J
MJ
Furman
Phillip A
PA
D000998:Antiviral Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D002460:Cell Line; D003562:Cytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D016174:Hepacivirus / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D008826:Microbial Sensitivity Tests; D010766:Phosphorylation; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors*; D012093:Replicon / Q000187:drug effects; D013329:Structure-Activity Relationship; D014544:Uridine Triphosphate / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*
D000998:Antiviral Agents; C504520:2'-deoxy-2'-fluoro-2'-C-methylcytidine; D003841:Deoxycytidine; D003562:Cytidine; C009131:pyrimidin-2-one beta-ribofuranoside; D012324:RNA-Dependent RNA Polymerase; D014544:Uridine Triphosphate