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Nonhelical leash and alpha-helical structures determine the potency of a peptide antagonist of human T-cell leukemia virus entry

Nonhelical leash and alpha-helical structures determine the potency of a peptide antagonist of human T-cell leukemia virus entry

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Authors

  • Antonis Mirsaliotis
  • Daniel Lamb
  • David W. Brighty

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    Info

    Original languageEnglish
    Pages4965-4973
    Number of pages9
    JournalJournal of Virology
    Journal publication dateMay 2008
    Journal number10
    Volume82
    DOIs
    StatePublished

    Abstract

    Viral fusion proteins mediate the entry of enveloped viral particles into cells by inducing fusion of the viral and target cell membranes. Activated fusion proteins undergo a cascade of conformational transitions and ultimately resolve into a compact trimer of hairpins or six-helix bundle structure, which pulls the interacting membranes together to promote lipid mixing. Significantly, synthetic peptides based on a C-terminal region of the trimer of hairpins are potent inhibitors of membrane fusion and viral entry, and such peptides are typically extensively alpha-helical. In contrast, an atypical peptide inhibitor of human T-cell leukemia virus (HTLV) includes alpha-helical and nonhelical leash segments. We demonstrate that both the C helix and C-terminal leash are critical to the inhibitory activities of these peptides. Amino acid side chains in the leash and C helix extend into deep hydrophobic pockets at the membrane-proximal end of the HTLV type 1 (HTLV-1) coiled coil, and these contacts are necessary for potent antagonism of membrane fusion. In addition, a single amino acid substitution within the inhibitory peptide improves peptide interaction with the core coiled coil and yields a peptide with enhanced potency. We suggest that the deep pockets on the coiled coil are ideal targets for small-molecule inhibitors of HTLV-1 entry into cells. Moreover, the extended nature of the HTLV-1-inhibitory peptide suggests that such peptides may be intrinsically amenable to modifications designed to improve inhibitory activity. Finally, we propose that leash-like mimetic peptides may be of value as entry inhibitors for other clinically important viral infections.

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