This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
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 Strizki, J. M.
Right arrow Articles by Baroudy, B. M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Strizki, J. M.
Right arrow Articles by Baroudy, B. M.

 Previous Article  |  Next Article 

Antimicrobial Agents and Chemotherapy, December 2005, p. 4911-4919, Vol. 49, No. 12
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.12.4911-4919.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Discovery and Characterization of Vicriviroc (SCH 417690), a CCR5 Antagonist with Potent Activity against Human Immunodeficiency Virus Type 1

Julie M. Strizki,1* Cecile Tremblay,2 Serena Xu,1 Lisa Wojcik,1 Nicole Wagner,1 Waldemar Gonsiorek,3 R. William Hipkin,3 Chuan-Chu Chou,3 Catherine Pugliese-Sivo,3 Yushi Xiao,4 Jayaram R. Tagat,4 Kathleen Cox,5 Tony Priestley,6 Steve Sorota,6 Wei Huang,7 Martin Hirsch,2 Gregory R. Reyes,1 and Bahige M. Baroudy1

Departments of Antiviral Therapy,1 Inflammation,3 Medicinal Chemistry,4 Drug Metabolism and Pharmacokinetics,5 Neurobiology, Schering-Plough Research Institute, Kenilworth, New Jersey 07033,6 Infectious Disease Division, Department of Medicine, Massachusetts General Hospital, Fruit Street, Boston, Massachusetts 02114,2 Monogram Biosciences, 345 Oyster Point Boulevard, South San Francisco, California 940807

Received 14 April 2005/ Returned for modification 7 July 2005/ Accepted 27 September 2005

Inhibiting human immunodeficiency virus type 1 (HIV-1) infection by blocking the host cell coreceptors CCR5 and CXCR4 is an emerging strategy for antiretroviral therapy. Currently, several novel coreceptor inhibitors are being developed in the clinic, and early results have proven promising. In this report, we describe a novel CCR5 antagonist, vicriviroc (formerly SCH-D or SCH 417690), with improved antiviral activity and pharmacokinetic properties compared to those of SCH-C, a previously described CCR5 antagonist. Like SCH-C, vicriviroc binds specifically to the CCR5 receptor and prevents infection of target cells by CCR5-tropic HIV-1 isolates. In antiviral assays, vicriviroc showed potent, broad-spectrum activity against genetically diverse and drug-resistant HIV-1 isolates and was consistently more active than SCH-C in inhibiting viral replication. This compound demonstrated synergistic anti-HIV activity in combination with drugs from all other classes of approved antiretrovirals. Competition binding assays revealed that vicriviroc binds with higher affinity to CCR5 than SCH-C. Functional assays, including inhibition of calcium flux, guanosine 5'-[35S]triphosphate exchange, and chemotaxis, confirmed that vicriviroc acts as a receptor antagonist by inhibiting signaling of CCR5 by chemokines. Finally, vicriviroc demonstrated diminished affinity for the human ether a-go-go related gene transcript ion channel compared to SCH-C, suggesting a reduced potential for cardiac effects. Vicriviroc represents a promising new candidate for the treatment of HIV-1 infection.

* Corresponding author. Mailing address: Schering-Plough Research Institute, Antiviral Therapy, 2015 Galloping Hill Road, K15, E405C/4945, Kenilworth, NJ 07033. Phone: (908) 740-4731. Fax: (908) 740-3032. E-mail: Julie.strizki{at}spcorp.com.

Antimicrobial Agents and Chemotherapy, December 2005, p. 4911-4919, Vol. 49, No. 12
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.12.4911-4919.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Murakami, T., Kumakura, S., Yamazaki, T., Tanaka, R., Hamatake, M., Okuma, K., Huang, W., Toma, J., Komano, J., Yanaka, M., Tanaka, Y., Yamamoto, N. (2009). The Novel CXCR4 Antagonist KRH-3955 Is an Orally Bioavailable and Extremely Potent Inhibitor of Human Immunodeficiency Virus Type 1 Infection: Comparative Studies with AMD3100. Antimicrob. Agents Chemother. 53: 2940-2948 [Abstract] [Full Text]  
  • Dudley, D. M., Wentzel, J. L., Lalonde, M. S., Veazey, R. S., Arts, E. J. (2009). Selection of a Simian-Human Immunodeficiency Virus Strain Resistant to a Vaginal Microbicide in Macaques. J. Virol. 83: 5067-5076 [Abstract] [Full Text]  
  • Nolan, K. M., Del Prete, G. Q., Jordan, A. P. O., Haggarty, B., Romano, J., Leslie, G. J., Hoxie, J. A. (2009). Characterization of a Human Immunodeficiency Virus Type 1 V3 Deletion Mutation That Confers Resistance to CCR5 Inhibitors and the Ability To Use Aplaviroc-Bound Receptor. J. Virol. 83: 3798-3809 [Abstract] [Full Text]  
  • Heredia, A., Latinovic, O., Gallo, R. C., Melikyan, G., Reitz, M., Le, N., Redfield, R. R. (2008). Reduction of CCR5 with low-dose rapamycin enhances the antiviral activity of vicriviroc against both sensitive and drug-resistant HIV-1. Proc. Natl. Acad. Sci. USA 105: 20476-20481 [Abstract] [Full Text]  
  • Schnell, G., Ince, W. L., Swanstrom, R. (2008). Identification and recovery of minor HIV-1 variants using the heteroduplex tracking assay and biotinylated probes. Nucleic Acids Res 36: e146-e146 [Abstract] [Full Text]  
  • Ptak, R. G., Gallay, P. A., Jochmans, D., Halestrap, A. P., Ruegg, U. T., Pallansch, L. A., Bobardt, M. D., de Bethune, M.-P., Neyts, J., De Clercq, E., Dumont, J.-M., Scalfaro, P., Besseghir, K., Wenger, R. M., Rosenwirth, B. (2008). Inhibition of Human Immunodeficiency Virus Type 1 Replication in Human Cells by Debio-025, a Novel Cyclophilin Binding Agent. Antimicrob. Agents Chemother. 52: 1302-1317 [Abstract] [Full Text]  
  • Kondru, R., Zhang, J., Ji, C., Mirzadegan, T., Rotstein, D., Sankuratri, S., Dioszegi, M. (2008). Molecular Interactions of CCR5 with Major Classes of Small-Molecule Anti-HIV CCR5 Antagonists. Mol. Pharmacol. 73: 789-800 [Abstract] [Full Text]  
  • Ji, C., Zhang, J., Dioszegi, M., Chiu, S., Rao, E., deRosier, A., Cammack, N., Brandt, M., Sankuratri, S. (2007). CCR5 Small-Molecule Antagonists and Monoclonal Antibodies Exert Potent Synergistic Antiviral Effects by Cobinding to the Receptor. Mol. Pharmacol. 72: 18-28 [Abstract] [Full Text]  
  • Ray, N., Harrison, J. E., Blackburn, L. A., Martin, J. N., Deeks, S. G., Doms, R. W. (2007). Clinical Resistance to Enfuvirtide Does Not Affect Susceptibility of Human Immunodeficiency Virus Type 1 to Other Classes of Entry Inhibitors. J. Virol. 81: 3240-3250 [Abstract] [Full Text]  
  • Baba, M., Miyake, H., Wang, X., Okamoto, M., Takashima, K. (2007). Isolation and Characterization of Human Immunodeficiency Virus Type 1 Resistant to the Small-Molecule CCR5 Antagonist TAK-652. Antimicrob. Agents Chemother. 51: 707-715 [Abstract] [Full Text]  
  • Whitcomb, J. M., Huang, W., Fransen, S., Limoli, K., Toma, J., Wrin, T., Chappey, C., Kiss, L. D. B., Paxinos, E. E., Petropoulos, C. J. (2007). Development and Characterization of a Novel Single-Cycle Recombinant-Virus Assay To Determine Human Immunodeficiency Virus Type 1 Coreceptor Tropism. Antimicrob. Agents Chemother. 51: 566-575 [Abstract] [Full Text]  
  • Aquaro, S., Svicher, V., Schols, D., Pollicita, M., Antinori, A., Balzarini, J., Perno, C. F. (2006). Mechanisms underlying activity of antiretroviral drugs in HIV-1-infected macrophages: new therapeutic strategies. J. Leukoc. Biol. 80: 1103-1110 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»