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Preclinical characteristics of the hepatitis C virus NS3/4A protease inhibitor ITMN-191 (R7227).

ABSTRACT: 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.

SUBMITTER: Seiwert SD

PROVIDER: S-EPMC2592891 | biostudies-literature | 2008 Dec

REPOSITORIES: biostudies-literature

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Preclinical characteristics of the hepatitis C virus NS3/4A protease inhibitor ITMN-191 (R7227).

Seiwert Scott D SD 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

Antimicrobial agents and chemotherapy 20080929 12

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 inhi ...[more]

PMID: 18824605

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Dataset Information

Preclinical characteristics of the hepatitis C virus NS3/4A protease inhibitor ITMN-191 (R7227).

Publications

Preclinical characteristics of the hepatitis C virus NS3/4A protease inhibitor ITMN-191 (R7227).

Similar Datasets

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