A 7-deaza-adenosine analog is a potent and selective inhibitor of hepatitis C virus replication with excellent pharmacokinetic properties.
Improved treatments for chronic hepatitis C virus (HCV) infection are needed due to the suboptimal response rates and deleterious side effects associated with current treatment options. The triphosphates of 2'-C-methyl-adenosine and 2'-C-methyl-guanosine were previously shown to be potent inhibitors of the HCV RNA-dependent RNA polymerase (RdRp) that is responsible for the replication of viral RNA in cells. Here we demonstrate that the inclusion of a 7-deaza modification in a series of purine nucleoside triphosphates results in an increase in inhibitory potency against the HCV RdRp and improved pharmacokinetic properties. Notably, incorporation of the 7-deaza modification into 2'-C-methyl-adenosine results in an inhibitor with a 20-fold-increased potency as the 5'-triphosphate in HCV RdRp assays while maintaining the inhibitory potency of the nucleoside in the bicistronic HCV replicon and with reduced cellular toxicity. In contrast, while 7-deaza-2'-C-methyl-GTP also displays enhanced inhibitory potency in enzyme assays, due to poor cellular penetration and/or metabolism, the nucleoside does not inhibit replication of a bicistronic HCV replicon in cell culture. 7-Deaza-2'-C-methyl-adenosine displays promising in vivo pharmacokinetics in three animal species, as well as an acute oral lethal dose in excess of 2,000 mg/kg of body weight in mice. Taken together, these data demonstrate that 7-deaza-2'-C-methyl-adenosine is an attractive candidate for further investigation as a potential treatment for HCV infection.
Olsen
David B
DB
Department of Biological Chemistry, Merck Research Laboratories, West Point, Pennsylvania 19486, USA. david_olsen@merck.com
Eldrup
Anne B
AB
Bartholomew
Linda
L
Bhat
Balkrishen
B
Bosserman
Michele R
MR
Ceccacci
Alessandra
A
Colwell
Lawrence F
LF
Fay
John F
JF
Flores
Osvaldo A
OA
Getty
Krista L
KL
Grobler
Jay A
JA
LaFemina
Robert L
RL
Markel
Eric J
EJ
Migliaccio
Giovanni
G
Prhavc
Marija
M
Stahlhut
Mark W
MW
Tomassini
Joanne E
JE
MacCoss
Malcolm
M
Hazuda
Daria J
DJ
Carroll
Steven S
SS
D000818:Animals; D000998:Antiviral Agents; D046508:Culture Techniques; D024882:Drug Resistance, Viral; D005260:Female; D005838:Genotype; D016174:Hepacivirus / Q000187:drug effects* / Q000201:enzymology; D006526:Hepatitis C / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism*; D006801:Humans; D019169:Jurkat Cells; D007928:Lethal Dose 50; D051379:Mice; D011062:Polynucleotide Adenylyltransferase / Q000378:metabolism; D012313:RNA / Q000096:biosynthesis; D012319:RNA Polymerase II / Q000378:metabolism; D012324:RNA-Dependent RNA Polymerase / Q000378:metabolism; D013936:Thymidine / Q000494:pharmacology; D014372:Tubercidin / Q000493:pharmacokinetics* / Q000494:pharmacology*; D014779:Virus Replication / Q000187:drug effects
D000998:Antiviral Agents; D012313:RNA; D012319:RNA Polymerase II; D011062:Polynucleotide Adenylyltransferase; D012324:RNA-Dependent RNA Polymerase; D014372:Tubercidin; D013936:Thymidine