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The Body PRO Covers: The 9th Conference on Retroviruses and Opportunistic Infections

Antiretroviral Chemotherapy: New Agents (Oral Abstract Session 4)

February 25, 2002

  • Identification and Characterization of a Novel Inhibitor of HIV-1 Entry -- I: Virology and Resistance
    Abstract 9
    Authored by P-F. Lin, B. Robinson, Y-F. Gong, K. Ricarrdi, Q. Guo, C. Deminie, R. Rose, T. Wang, N. Meanwell, Z. Yang, H. Wang, T. Zhang, and R. Colonno (Bristol-Myers Squibb Pharmaceutical Res. Inst., Wallingford, CT)
    View the original abstract
  • Identification and Characterization of a Novel Inhibitor of HIV-1 Entry -- II: Mechanism of Action
    Abstract 10
    Authored by P-F. Lin, K. Guo, R. Fridell, H-T. Ho, G. Yamanaka, and R. Colonno (Bristol-Myers Squibb Pharmaceutical Res. Inst., Wallingford, CT)
    View the original abstract


All of the approved agents for treatment of HIV inhibit one of two processes in viral replication, either reverse transcriptase (the NRTIs and the NNRTIs) or protease (protease inhibitors). Two additional areas of extensive investigation for drug development are inhibitors of viral entry and viral integrase. Today's presentation from R. Colonno of Bristol-Myers Squibb outlined his group's effort to identify and characterize a new inhibitor of viral entry.

HIV entry into CD4 cells can be divided into three phases:

  1. binding of the envelope protein gp120 to the CD4 receptor;

  2. after a conformational change in gp120, attachment to the co-receptor CCR5 or CXCR4; and

  3. fusion of viral and cell membranes.

(Of note, antiviral activity has already been demonstrated for inhibitors of CCR5 and viral fusion with the agents SCH-C and T-20, respectively.)

Colonno's group screened more than 100,000 compounds for anti-HIV activity, settling on several candidates for further development. The leading candidate emerging in this search is BMS-806, based on several desirable features, including good HIV specificity, low cytotoxicity, modest protein binding and oral bioavailability.

Further characterization of the actual mechanism of action of BMS-806 identified that it acts at an earlier stage in HIV entry than SCH-C and T-20, specifically at the binding of gp120 to the CD4 receptor. Gp120 is known to be a highly variable area of HIV, subject to great differences based on viral clade, or strain. Indeed, in vitro antiviral activity of BMS-806 was confirmed for clades A, B (the most common in the United States and Western Europe), C and D, but not for E, F, G and O. Furthermore, through passage experiments where HIV and cells are exposed to the compound at multiple concentrations, viruses that are resistant to BMS-806 readily emerge, with mutations that cluster around the CD4 binding site. Not surprisingly, these resistant isolates show no cross-resistance with existing compounds, and the converse is true as well. Early animal toxicity studies in dogs and rats show no important adverse effects.

The main importance of this presentation is that another drug target has been identified, namely the first step in virus entry -- gp120 binding to the CD4 molecule. While BMS-806 is still in a relatively early stage of development, the compound's many favorable characteristics and novel mechanism of action are both encouraging. It is highly likely that combination regimens that block different aspects of the viral entry process will ultimately prove to be more potent and less prone to resistance.


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This article was provided by TheBodyPRO.com. It is a part of the publication The 9th Conference on Retroviruses and Opportunistic Infections.
 



Please note: Knowledge about HIV changes rapidly. Note the date of this summary's publication, and before treating patients or employing any therapies described in these materials, verify all information independently. If you are a patient, please consult a doctor or other medical professional before acting on any of the information presented in this summary. For a complete listing of our most recent conference coverage, click here.
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