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Issue 4, 2010
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Affinity selection and sequence-activity relationships of HIV-1membrane fusioninhibitors directed at the drug-resistant variants

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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.

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

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Publication details

The article was received on 29 Jun 2010, accepted on 22 Jul 2010 and first published on 20 Aug 2010


Article type: Concise Article
DOI: 10.1039/C0MD00091D
Med. Chem. Commun., 2010,1, 276-281

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

    S. Oishi, K. Watanabe, S. Ito, M. Tanaka, H. Nishikawa, H. Ohno, K. Shimane, K. Izumi, Y. Sakagami, E. N. Kodama, M. Matsuoka, A. Asai and N. Fujii, Med. Chem. Commun., 2010, 1, 276
    DOI: 10.1039/C0MD00091D

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