Journal article
Structural Determinants for Affinity Enhancement of a Dual Antagonist Peptide Entry Inhibitor of Human Immunodeficiency Virus Type-1
Journal of medicinal chemistry, v 51(9), pp 2638-2647
08 May 2008
PMID: 18402432
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Structure-activity correlations were investigated for substituted peptide conjugates that function as dual receptor site antagonists of HIV-1 gp120. A series of peptide conjugates were constructed via click reaction of both aryl and alkyl acetylenes with an internally-incorporated azidoproline 6 derived from the parent peptide
1
(12p1, RINNIPWSEAMM). Compared to
1
, many of these conjugates were found to exhibit several orders of magnitude increase in both affinity for HIV-1 gp120 and inhibition potencies at both the CD4 and co-receptor binding sites of gp120. We sought to determine structural factors in the added triazole grouping responsible for the increased binding affinity and antiviral activity of the dual inhibitor conjugates. We measured peptide conjugate potencies in both kinetic and cell infection assays. High affinity was sterically specific, being exhibited by the
cis
but not the
trans
triazole. The results demonstrate that aromatic, hydrophobic and steric features in the residue 6 side-chain are important for increased affinity and inhibition. Optimizing these features provides a basis for developing gp120 dual inhibitors into peptidomimetic and increasingly smaller molecular weight entry antagonist leads.
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Details
- Title
- Structural Determinants for Affinity Enhancement of a Dual Antagonist Peptide Entry Inhibitor of Human Immunodeficiency Virus Type-1
- Creators
- Hosahudya Gopi - Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA 19102M Umashankara - Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA 19102Vanessa Pirrone - Department of Microbiology and Immunology, and Center for Molecular Therapeutics, Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, Philadelphia, PA 19102Judith LaLonde - Department of Chemistry, Bryn Mawr College, Bryn Mawr, PANavid Madani - Dana-Farber Cancer Institute, Division of AIDS, Harvard Medical School, Boston, MA 02115Ferit Tuzer - Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA 19102Sabine Baxter - Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA 19102Isaac Zentner - Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA 19102Simon Cocklin - Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA 19102Navneet Jawanda - Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA 19102Shendra R Miller - Department of Microbiology and Immunology, and Center for Molecular Therapeutics, Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, Philadelphia, PA 19102Arne Schön - Department of Biology, The Johns Hopkins University, Baltimore, MD 21218Jeffrey C Klein - Department of Biology, The Johns Hopkins University, Baltimore, MD 21218Ernesto Freire - Department of Biology, The Johns Hopkins University, Baltimore, MD 21218Fred C Krebs - Department of Microbiology and Immunology, and Center for Molecular Therapeutics, Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, Philadelphia, PA 19102Amos B Smith - Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104Joseph Sodroski - Dana-Farber Cancer Institute, Division of AIDS, Harvard Medical School, Boston, MA 02115Irwin Chaiken - Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA 19102
- Publication Details
- Journal of medicinal chemistry, v 51(9), pp 2638-2647
- Publisher
- American Chemical Society; Washington, DC
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology; Microbiology and Immunology
- Web of Science ID
- WOS:000255500000009
- Scopus ID
- 2-s2.0-42949103034
- Other Identifier
- 991014877692804721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Chemistry, Medicinal