Highly specific inhibition of leukaemia virus membrane fusion by interaction of peptide antagonists with a conserved region of the coiled coil of envelope

Daniel Lamb, Alexander W. Schuettelkopf, Daan M. F. van Aalten, David W. Brighty (Lead / Corresponding author)

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    Abstract

    Background: Human T-cell leukaemia virus (HTLV-1) and bovine leukaemia virus (BLV) entry into cells is mediated by envelope glycoprotein catalyzed membrane fusion and is achieved by folding of the transmembrane glycoprotein (TM) from a rod-like pre-hairpin intermediate to a trimer-ofhairpins. For HTLV-1 and for several virus groups this process is sensitive to inhibition by peptides that mimic the C-terminal a-helical region of the trimer-of-hairpins.

    Results: We now show that amino acids that are conserved between BLV and HTLV-1 TM tend to map to the hydrophobic groove of the central triple-stranded coiled coil and to the leash and C-terminal a-helical region (LHR) of the trimer-of-hairpins. Remarkably, despite this conservation, BLV envelope was profoundly resistant to inhibition by HTLV-1-derived LHR-mimetics. Conversely, a BLV LHR-mimetic peptide antagonized BLV envelope-mediated membrane fusion but failed to inhibit HTLV-1-induced fusion. Notably, conserved leucine residues are critical to the inhibitory activity of the BLV LHR-based peptides. Homology modeling indicated that hydrophobic residues in the BLV LHR likely make direct contact with a pocket at the membrane-proximal end of the core coiled-coil and disruption of these interactions severely impaired the activity of the BLV inhibitor. Finally, the structural predictions assisted the design of a more potent antagonist of BLV membrane fusion.

    Conclusion: A conserved region of the HTLV-1 and BLV coiled coil is a target for peptide inhibitors of envelope-mediated membrane fusion and HTLV-1 entry. Nevertheless, the LHR-based inhibitors are highly specific to the virus from which the peptide was derived. We provide a model structure for the BLV LHR and coiled coil, which will facilitate comparative analysis of leukaemia virus TM function and may provide information of value in the development of improved, therapeutically relevant, antagonists of HTLV-1 entry into cells.

    Original languageEnglish
    Article number70
    Pages (from-to)-
    Number of pages14
    JournalRetrovirology
    Volume5
    DOIs
    Publication statusPublished - 4 Aug 2008

    Keywords

    • SYNTHETIC PEPTIDE
    • CRYSTAL-STRUCTURE
    • FUNCTIONAL DOMAINS
    • POTENT INHIBITOR
    • DISULFIDE-BOND
    • CORE STRUCTURE
    • VIRAL FUSION
    • EBOLA-VIRUS
    • CELL FUSION
    • HIV-1 GP41

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