The active core in a triazole peptide dual-site antagonist of HIV-1 gp120

Muddegowda Umashankara, Karyn McFadden, Isaac Zentner, Arne Schön, Srivats Rajagopal, Ferit Tuzer, Syna A. Kuriakose, Mark Contarino, Judith Lalonde, Ernesto I Freire, Irwin Chaiken

Research output: Contribution to journalArticle

Abstract

In an effort to identify broadly active inhibitors of HIV-1 entry into host cells, we previously reported a family of dodecamer triazole-peptide conjugates with nanomolar affinity for the viral surface protein gp120. This peptide class exhibits potent antiviral activity and the capacity to simultaneously inhibit interaction of the viral envelope protein with both CD4 and co-receptor. In this investigation, we minimized the structural complexity of the lead triazole inhibitor HNG-156 (peptide 1) to explore the limits of the pharmacophore that enables dual antagonism and to improve opportunities for peptidomimetic design. Truncations of both carboxy- and amino-terminal residues from the parent 12-residue peptide 1 were found to have minimal effects 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 that define 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 bonding. The results of this work argue that the pharmacophore for dual antagonism is structurally limited, thereby 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. The core of the matter: Optimization of a previously identified 12-mer peptide HIV-1 entry inhibitor led to the discovery of the minimal amino acid sequence essential for dual antagonism and antiviral activity. A pentapeptide of sequence 3-7 in the parent compound (shown) exhibits the functional signature of the 12-mer. This suggests that the target epitope on gp120 for dual-site antagonism is structurally limited and amenable to targeting by small molecules or peptidomimetics.

Original languageEnglish (US)
Pages (from-to)1871-1879
Number of pages9
JournalChemMedChem
Volume5
Issue number11
DOIs
StatePublished - Nov 8 2010

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Keywords

  • click chemistry
  • entry inhibitors
  • HIV-1
  • peptide triazoles
  • surface plasmon resonance

ASJC Scopus subject areas

  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Organic Chemistry
  • Molecular Medicine

Cite this

Umashankara, M., McFadden, K., Zentner, I., Schön, A., Rajagopal, S., Tuzer, F., Kuriakose, S. A., Contarino, M., Lalonde, J., Freire, E. I., & Chaiken, I. (2010). The active core in a triazole peptide dual-site antagonist of HIV-1 gp120. ChemMedChem, 5(11), 1871-1879. https://doi.org/10.1002/cmdc.201000222