Affinity selection and sequence-activity relationships of HIV-1 membrane fusion inhibitors directed at the drug-resistant variants

Shinya Oishi, Kentaro Watanabe, Saori Ito, Michinori Tanaka, Hiroki Nishikawa, Hiroaki Ohno, Kazuki Shimane, Kazuki Izumi, Yasuko Sakagami, Eiichi N. Kodama, Masao Matsuoka, Akira Asai, Nobutaka Fujii

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)

Abstract

Enfuvirtide is the first approved membrane fusion inhibitor against HIV-1. Although this drug is effective against multi-drug resistant strains, the emergence of enfuvirtide-resistant strains has been reported in patients who have received an enfuvirtide-containing regimen. Based on the high affinity of synthetic HIV-1 gp41 C-terminal heptad repeat (C-HR) peptides to the counterpart trimeric N-terminal heptad repeat (N-HR) coiled-coil structure, a novel screening approach has been established to facilitate the identification of potent fusion inhibitors against wild-type and enfuvirtide-resistant HIV-1. In this process, affinity selection using histidine-tagged N-HR peptides with the sequences derived from wild-type and resistant strains efficiently captured potent inhibitory peptides from a pool of highly water-soluble C-HR peptides with α-helix-inducible motifs. A highly potent peptide was found from a single amino acid substitution observed in an enfuvirtide-resistant variant as well as peptides with unprecedented modifications at the mutated site.

Original languageEnglish
Pages (from-to)276-281
Number of pages6
JournalMedChemComm
Volume1
Issue number4
DOIs
Publication statusPublished - 2010 Oct

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Pharmacology
  • Pharmaceutical Science
  • Drug Discovery
  • Organic Chemistry

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