This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Supplemental material
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow E-mail this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Seiwert, S. D.
Right arrow Articles by Blatt, L. M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Seiwert, S. D.
Right arrow Articles by Blatt, L. M.

 Previous Article  |  Next Article 

Antimicrobial Agents and Chemotherapy, December 2008, p. 4432-4441, Vol. 52, No. 12
0066-4804/08/$08.00+0     doi:10.1128/AAC.00699-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Preclinical Characteristics of the Hepatitis C Virus NS3/4A Protease Inhibitor ITMN-191 (R7227) {triangledown} ,{dagger}

Scott D. Seiwert,1* Steven W. Andrews,2 Yutong Jiang,2 Vladimir Serebryany,1 Hua Tan,1 Karl Kossen,1 P. T. Ravi Rajagopalan,1 Shawn Misialek,1 Sarah K. Stevens,1 Antitsa Stoycheva,1 Jin Hong,1 Sharlene R. Lim,1 Xiaoli Qin,1 Robert Rieger,2 Kevin R. Condroski,2 Hailong Zhang,2 Mary Geck Do,2 Christine Lemieux,2 Gary P. Hingorani,2 Dylan P. Hartley,2 John A. Josey,2 Lin Pan,1 Leonid Beigelman,1 and Lawrence M. Blatt1

InterMune, Incorporated, 3280 Bayshore Boulevard, Brisbane, California 94005,1 Array Biopharma, Incorporated, 3200 Walnut Street, Boulder, Colorado 803012

Received 28 May 2008/ Returned for modification 7 August 2008/ Accepted 19 September 2008

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.

* Corresponding author. Mailing address: InterMune, Inc., 3280 Bayshore Blvd., Brisbane, CA 94005. Phone: (415) 466-2250. Fax: (415) 466-2350. E-mail: sseiwert{at}intermune.com

{triangledown} Published ahead of print on 29 September 2008.

{dagger} Supplemental material for this article may be found at http://aac.asm.org/.

Antimicrobial Agents and Chemotherapy, December 2008, p. 4432-4441, Vol. 52, No. 12
0066-4804/08/$08.00+0     doi:10.1128/AAC.00699-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Liverton, N. J., Carroll, S. S., DiMuzio, J., Fandozzi, C., Graham, D. J., Hazuda, D., Holloway, M. K., Ludmerer, S. W., McCauley, J. A., McIntyre, C. J., Olsen, D. B., Rudd, M. T., Stahlhut, M., Vacca, J. P. (2010). MK-7009, a Potent and Selective Inhibitor of Hepatitis C Virus NS3/4A Protease. Antimicrob. Agents Chemother. 54: 305-311 [Abstract] [Full Text]  


Copyright © 2010 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»