An NS3 protease inhibitor with antiviral effects in humans infected with hepatitis C virus.
Hepatitis C virus (HCV) infection is a serious cause of chronic liver disease worldwide with more than 170 million infected individuals at risk of developing significant morbidity and mortality. Current interferon-based therapies are suboptimal especially in patients infected with HCV genotype 1, and they are poorly tolerated, highlighting the unmet medical need for new therapeutics. The HCV-encoded NS3 protease is essential for viral replication and has long been considered an attractive target for therapeutic intervention in HCV-infected patients. Here we identify a class of specific and potent NS3 protease inhibitors and report the evaluation of BILN 2061, a small molecule inhibitor biologically available through oral ingestion and the first of its class in human trials. Administration of BILN 2061 to patients infected with HCV genotype 1 for 2 days resulted in an impressive reduction of HCV RNA plasma levels, and established proof-of-concept in humans for an HCV NS3 protease inhibitor. Our results further illustrate the potential of the viral-enzyme-targeted drug discovery approach for the development of new HCV therapeutics.
Lamarre
Daniel
D
Department of Biological Sciences Boehringer Ingelheim (Canada) Ltd, Laval, Québec, H7S 2G5, Canada. dlamarre@lav.boehringer-ingelheim.com
Anderson
Paul C
PC
Bailey
Murray
M
Beaulieu
Pierre
P
Bolger
Gordon
G
Bonneau
Pierre
P
Bös
Michael
M
Cameron
Dale R
DR
Cartier
Mireille
M
Cordingley
Michael G
MG
Faucher
Anne-Marie
AM
Goudreau
Nathalie
N
Kawai
Stephen H
SH
Kukolj
George
G
Lagacé
Lisette
L
LaPlante
Steven R
SR
Narjes
Hans
H
Poupart
Marc-André
MA
Rancourt
Jean
J
Sentjens
Roel E
RE
St George
Roger
R
Simoneau
Bruno
B
Steinmann
Gerhard
G
Thibeault
Diane
D
Tsantrizos
Youla S
YS
Weldon
Steven M
SM
Yong
Chan-Loi
CL
Llinàs-Brunet
Montse
M
D000284:Administration, Oral; D000998:Antiviral Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D002219:Carbamates / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D004311:Double-Blind Method; D016174:Hepacivirus / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics / Q000502:physiology*; D006526:Hepatitis C / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D047028:Macrocyclic Compounds; D008297:Male; D020815:Polyproteins / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011804:Quinolines; D015842:Serine Proteinase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D013844:Thiazoles / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D019562:Viral Load; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014764:Viral Proteins / Q000378:metabolism; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
D000998:Antiviral Agents; D002219:Carbamates; D047028:Macrocyclic Compounds; D020815:Polyproteins; D011804:Quinolines; D015842:Serine Proteinase Inhibitors; D013844:Thiazoles; D017361:Viral Nonstructural Proteins; D014764:Viral Proteins; C479555:BILN 2061; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases