Structural determinants for affinity enhancement of a dual antagonist peptide entry inhibitor of human immunodeficiency virus type-1

Hosahudya Gopi, M. Umashankara, Vanessa Pirrone, Judith LaLonde, Navid Madani, Ferit Tuzer, Sabine Baxter, Isaac Zentner, Simon Cocklin, Navneet Jawanda, Shendra R. Miller, Arne Schön, Jeffrey C. Klein, Ernesto Freire, Fred C. Krebs, Amos B. Smith, Joseph Sodroski, Irwin Chaiken

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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 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.

Original languageEnglish (US)
Pages (from-to)2638-2647
Number of pages10
JournalJournal of medicinal chemistry
Volume51
Issue number9
DOIs
StatePublished - May 8 2008

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ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Gopi, H., Umashankara, M., Pirrone, V., LaLonde, J., Madani, N., Tuzer, F., Baxter, S., Zentner, I., Cocklin, S., Jawanda, N., Miller, S. R., Schön, A., Klein, J. C., Freire, E., Krebs, F. C., Smith, A. B., Sodroski, J., & Chaiken, I. (2008). Structural determinants for affinity enhancement of a dual antagonist peptide entry inhibitor of human immunodeficiency virus type-1. Journal of medicinal chemistry, 51(9), 2638-2647. https://doi.org/10.1021/jm070814r