Preclinical characteristics of the hepatitis C virus NS3/4A protease inhibitor ITMN-191 (R7227).
Future treatments for chronic hepatitis C virus (HCV) infection are likely to include agents that target viral components directly. Here, the preclinical characteristics of ITMN-191, a peptidomimetic inhibitor of the NS3/4A protease of HCV, are described. ITMN-191 inhibited a reference genotype 1 NS3/4A protein in a time-dependent fashion, a hallmark of an inhibitor with a two-step binding mechanism and a low dissociation rate. Under preequilibrium conditions, 290 pM ITMN-191 half-maximally inhibited the reference NS3/4A protease, but a 35,000-fold-higher concentration did not appreciably inhibit a panel of 79 proteases, ion channels, transporters, and cell surface receptors. Subnanomolar biochemical potency was maintained against NS3/4A derived from HCV genotypes 4, 5, and 6, while single-digit nanomolar potency was observed against NS3/4A from genotypes 2b and 3a. Dilution of a preformed enzyme inhibitor complex indicated ITMN-191 remained bound to and inhibited NS3/4A for more than 5 h after its initial association. In cell-based potency assays, half-maximal reduction of genotype 1b HCV replicon RNA was afforded by 1.8 nM; 45 nM eliminated the HCV replicon from cells. Peginterferon alfa-2a displayed a significant degree of antiviral synergy with ITMN-191 and reduced the concentration of ITMN-191 required for HCV replicon elimination. A 30-mg/kg of body weight oral dose administered to rats or monkeys yielded liver concentrations 12 h after dosing that exceeded the ITMN-191 concentration required to eliminate replicon RNA from cells. These preclinical characteristics compare favorably to those of other inhibitors of NS3/4A in clinical development and therefore support the clinical investigation of ITMN-191 for the treatment of chronic hepatitis C.
Seiwert
Scott D
SD
InterMune, Inc., 3280 Bayshore Blvd., Brisbane, CA 94005, USA. sseiwert@intermune.com
Andrews
Steven W
SW
Jiang
Yutong
Y
Serebryany
Vladimir
V
Tan
Hua
H
Kossen
Karl
K
Rajagopalan
P T Ravi
PT
Misialek
Shawn
S
Stevens
Sarah K
SK
Stoycheva
Antitsa
A
Hong
Jin
J
Lim
Sharlene R
SR
Qin
Xiaoli
X
Rieger
Robert
R
Condroski
Kevin R
KR
Zhang
Hailong
H
Do
Mary Geck
MG
Lemieux
Christine
C
Hingorani
Gary P
GP
Hartley
Dylan P
DP
Josey
John A
JA
Pan
Lin
L
Beigelman
Leonid
L
Blatt
Lawrence M
LM
D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D045744:Cell Line, Tumor; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D016174:Hepacivirus / Q000187:drug effects* / Q000201:enzymology* / Q000235:genetics / Q000502:physiology; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D008099:Liver / Q000378:metabolism; D008252:Macaca fascicularis; D011092:Polyethylene Glycols / Q000494:pharmacology; D011480:Protease Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D011994:Recombinant Proteins; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D014764:Viral Proteins / Q000037:antagonists & inhibitors*; D014779:Virus Replication / Q000187:drug effects; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
D000998:Antiviral Agents; D002352:Carrier Proteins; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D047908:Intracellular Signaling Peptides and Proteins; D011092:Polyethylene Glycols; D011480:Protease Inhibitors; D011994:Recombinant Proteins; D017361:Viral Nonstructural Proteins; D014764:Viral Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C455041:NS4A cofactor peptide, Hepatitis C virus; C100416:peginterferon alfa-2a