Structural Determinants for Affinity Enhancement of a Dual Antagonist Peptide Entry Inhibitor of Human Immunodeficiency Virus Type-1
| Autor: | Vanessa Pirrone, Shendra R. Miller, Simon Cocklin, Sabine Baxter, Ferit Tuzer, Irwin Chaiken, Judith M. LaLonde, M. Umashankara, Jeffrey C. Klein, Navneet Jawanda, Fred C. Krebs, Arne Schön, Amos B. Smith, Joseph Sodroski, Ernesto Freire, Navid Madani, Hosahudya N. Gopi, Isaac Zentner |
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| Rok vydání: | 2008 |
| Předmět: |
Anti-HIV Agents
Stereochemistry Stereoisomerism Peptide HIV Antibodies HIV Envelope Protein gp120 Article Cell Line Structure-Activity Relationship chemistry.chemical_compound Drug Discovery medicine Peptide synthesis Humans Structure–activity relationship Binding site Receptor chemistry.chemical_classification Binding Sites Molecular Mimicry Antibodies Monoclonal Triazoles Virus Internalization Entry inhibitor chemistry CD4 Antigens HIV-1 Molecular Medicine Peptides Protein Binding medicine.drug Conjugate |
| Zdroj: | Journal of Medicinal Chemistry. 51:2638-2647 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | 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 coreceptor 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. |
| Databáze: | OpenAIRE |
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