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J. Virol. doi:10.1128/JVI.02458-07
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Non-helical Leash and -helical Structures Determine the Potency of a Peptide Antagonist of Human T Cell Leukaemia Virus Entry

From The Biomedical Research Centre; Ninewells Hospital and Medical School, The University, Dundee DD1 9SY, Scotland, UK

^* To whom correspondence should be addressed. Email: d.w.brighty{at}dundee.ac.uk.

	Abstract

Viral fusion proteins mediate 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 to 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 -helical. In contrast, an atypical peptide inhibitor of human T cell leukaemia virus includes -helical and non-helical leash segments. We now demonstrate that both the C helix and C-terminal leash are critical to the inhibitory activity 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-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.