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Protein-Protein Interaction Targets to Inhibit HIV-1 Infection

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Protein-Protein Interactions

Part of the book series: Topics in Medicinal Chemistry ((TMC,volume 8))

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Abstract

Efforts to interfere with four key protein-protein interactions in the HIV-1 lifecycle with the goal of achieving clinically-relevant, orally administered HIV-1 therapies are reviewed. These four targets: the HIV-1 gp120/human CD4 interaction, the HIV-1 gp41 six-helix bundle formation, the human LEDGF/p75-integrase interaction, and HIV-1 protease dimerization each present unique challenges to the discovery of viable small molecule inhibitors. Background information from the literature is provided. A class of inhibitors which target gp120 from which an orally dosed member has been advanced into Phase II clinical studies as well as other small molecule approaches to disrupt the gp120/CD4 interaction are discussed. The unrealized efforts to find a small-molecule inhibitor of gp41 six-helix bundle formation that is suitable for clinical studies are described, including a summary of the work on effective, peptidic inhibitors that lack the properties needed for oral use. An overview of the progress to identify small molecule inhibitors of the LEDGF/HIV-1 p75-integrase interaction and the dimerization of the HIV-1 protease enzyme describes the preclinical compounds of greatest interest and discusses the rationale behind their design/activity.

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Authors and Affiliations

  1. Department of Medicinal Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT, 06492, USA

    John F. Kadow, Nicholas A. Meanwell, Richard Pracitto, Michael A. Walker & Kap-Sun Yeung

  2. Department of Computer-Aided Drug Design, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT, 06492, USA

    David R. Langley

Authors
  1. John F. Kadow
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  2. David R. Langley
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  3. Nicholas A. Meanwell
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  4. Richard Pracitto
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  5. Michael A. Walker
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  6. Kap-Sun Yeung
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Corresponding author

Correspondence to John F. Kadow .

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Editors and Affiliations

  1. , Global Pharmaceutical R & D, Abbott Laboratories, Dept R4N6 / Bldg AP10-3, Abbott Park Rd 100, Abbott Park, 60064, Illinois, USA

    Michael D. Wendt

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© 2012 Springer-Verlag Berlin Heidelberg

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Kadow, J.F., Langley, D.R., Meanwell, N.A., Pracitto, R., Walker, M.A., Yeung, KS. (2012). Protein-Protein Interaction Targets to Inhibit HIV-1 Infection. In: Wendt, M. (eds) Protein-Protein Interactions. Topics in Medicinal Chemistry, vol 8. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-28965-1_4

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