Journal article
Active Core in a Triazole Peptide Dual Site Antagonist of HIV-1 gp120
ChemMedChem, v 5(11), pp 1871-1879
08 Nov 2010
PMID: 20677318
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
In an effort to identify broadly active inhibitors of HIV-1 entry into host cells, we had previously reported a family of dodecamer triazole-peptide conjugates with nanomolar affinity for viral surface protein gp120. This class of peptides exhibits potent antiviral activity and the capacity to simultaneously inhibit interaction of viral envelope protein with both CD4 and co-receptor. In the current investigation, we used minimization of structural complexity of the lead triazole inhibitor HNG-156 (peptide
1
) in order to explore the limits of the pharmacophore that enables dual antagonism and to improve opportunities for peptidomimetic design. Truncations of both carboxyl- and amino-terminal residues of the initial 12 amino acid residues of peptide
1
were found to have minimal effect on both affinity and antiviral activity. In contrast, the central triazole Pro-Trp cluster at residues 6 and 7 with ferrocenyl-triazole-Pro (Ftp) was found to be critical for bioactivity. Amino terminal residues distal to the central triazole Pro-Trp sequence tolerated decreasing degrees of side chain variation upon approaching the central cluster. A peptide fragment containing residues 3-7 (Asn-Asn-Ile-Ftp-Trp) exhibited substantial direct binding affinity, antiviral potency, dual receptor site antagonism and induction of gp120 structuring, all properties defining the functional signature of the parent compound
1
. This active core contains a stereochemically specific hydrophobic triazole-Pro-Trp cluster, with a short N-terminal peptide extension providing groups for potential main chain and side chain hydrogen binding. The results of this work argue that the pharmacophore for dual antagonism is structurally limited, enhancing the potential to develop minimized peptidomimetic HIV-1 entry inhibitors that simultaneously suppress binding of envelope protein to both of its host cell receptors. The results also argue that the target epitope on gp120 is relatively small, pointing to a localized allosteric inhibition site in the HIV-1 envelope that could be targeted for small-molecule inhibitor discovery.
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Details
- Title
- Active Core in a Triazole Peptide Dual Site Antagonist of HIV-1 gp120
- Creators
- Muddegowda Umashankara - Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, Pennsylvania 19102 (USA)Karyn McFadden - Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, Pennsylvania 19102 (USA)Isaac Zentner - Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, Pennsylvania 19102 (USA)Arne Schön - Department of Biology, The Johns Hopkins University, Baltimore, Maryland 21218 (USA)Srivats Rajagopal - Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, Pennsylvania 19102 (USA)Ferit Tuzer - Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, Pennsylvania 19102 (USA)Syna A Kuriakose - Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, Pennsylvania 19102 (USA)Mark Contarino - Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, Pennsylvania 19102 (USA)Judith LaLonde - Department of Chemistry, Bryn Mawr College, Bryn Mawr, PA 19010 (USA)Ernesto Freire - Department of Biology, The Johns Hopkins University, Baltimore, Maryland 21218 (USA)Irwin Chaiken - Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, Pennsylvania 19102 (USA)
- Publication Details
- ChemMedChem, v 5(11), pp 1871-1879
- Publisher
- Wiley
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology
- Web of Science ID
- WOS:000284585500010
- Scopus ID
- 2-s2.0-78349264989
- Other Identifier
- 991014877792004721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Chemistry, Medicinal
- Pharmacology & Pharmacy