TMC647055, a potent nonnucleoside hepatitis C virus NS5B polymerase inhibitor with cross-genotypic coverage.
Hepatitis C virus (HCV) infection is a major global health burden and is associated with an increased risk of liver cirrhosis and hepatocellular carcinoma. There remains an unmet medical need for efficacious and safe direct antivirals with complementary modes of action for combination in treatment regimens to deliver a high cure rate with a short duration of treatment for HCV patients. Here we report the in vitro inhibitory activity, mode of action, binding kinetics, and resistance profile of TMC647055, a novel and potent nonnucleoside inhibitor of the HCV NS5B RNA-dependent RNA polymerase. In vitro combination studies with an HCV NS3/4A protease inhibitor demonstrated potent suppression of HCV RNA replication, confirming the potential for combination of these two classes in the treatment of chronic HCV infection. TMC647055 is a potent nonnucleoside NS5B polymerase inhibitor of HCV replication with a promising in vitro biochemical, kinetic, and virological profile that is currently undergoing clinical evaluation.
Janssen Infectious Diseases, Beerse, Belgium.
Benoit
B
Devogelaere
Jan Martin
JM
Berke
Leen
L
Vijgen
Pascale
P
Dehertogh
Els
E
Fransen
Erna
E
Cleiren
Liesbet
L
van der Helm
Origène
O
Nyanguile
Abdellah
A
Tahri
Katie
K
Amssoms
Oliver
O
Lenz
Maxwell D
MD
Cummings
Reginald F
RF
Clayton
Sandrine
S
Vendeville
Pierre
P
Raboisson
Kenneth A
KA
Simmen
Gregory C
GC
Fanning
Tse-I
TI
Lin
D000998:Antiviral Agents / Q000494:pharmacology*; D002460:Cell Line; D003001:Cloning, Molecular; D004338:Drug Combinations; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004926:Escherichia coli / Q000235:genetics; D017930:Genes, Reporter; D016174:Hepacivirus / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics / Q000254:growth & development; D019698:Hepatitis C, Chronic / Q000188:drug therapy / Q000821:virology; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology*; D006801:Humans; D010957:Plasmids; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology*; D014162:Transfection; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
D000998:Antiviral Agents; D004338:Drug Combinations; D004791:Enzyme Inhibitors; D006576:Heterocyclic Compounds, 4 or More Rings; D012324:RNA-Dependent RNA Polymerase; D011994:Recombinant Proteins; D013449:Sulfonamides; D017361:Viral Nonstructural Proteins; C575713:27-cyclohexyl-12,13,16,17-tetrahydro-22-methoxy-11,17-dimethyl-10,10-dioxide-2,19-methano-3,7:4,1-dimetheno-1H,11H-14,10,2,9,11,17-benzoxathiatetraazacyclo docosine-8,18(9H,15H)-dione; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C087036:NS-5 protein, hepatitis C virus