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Journal of Virology, May 2008, p. 4965-4973, Vol. 82, No. 10
0022-538X/08/$08.00+0     doi:10.1128/JVI.02458-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Nonhelical Leash and -Helical Structures Determine the Potency of a Peptide Antagonist of Human T-Cell Leukemia Virus Entry

Antonis Mirsaliotis, Daniel Lamb, and David W. Brighty^*

Biomedical Research Centre, Ninewells Hospital and Medical School, The University, Dundee DD1 9SY, Scotland, United Kingdom

Received 15 November 2007/ Accepted 20 February 2008

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 -helical. In contrast, an atypical peptide inhibitor of human T-cell leukemia virus (HTLV) includes -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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* Corresponding author. Mailing address: The Biomedical Research Centre, Ninewells, Hospital and Medical School, The University, Dundee DD1 9SY, Scotland, United Kingdom. Phone: 44 1382 660111. Fax: 44 1382 669993. E-mail: d.w.brighty{at}dundee.ac.uk

Published ahead of print on 27 February 2008.

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Journal of Virology, May 2008, p. 4965-4973, Vol. 82, No. 10
0022-538X/08/$08.00+0     doi:10.1128/JVI.02458-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

This article has been cited by other articles:

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• Lamb, D., Mirsaliotis, A., Kelly, S. M., Brighty, D. W. (2009). Basic Residues Are Critical to the Activity of Peptide Inhibitors of Human T Cell Leukemia Virus Type 1 Entry. J. Biol. Chem. 284: 6575-6584 [Abstract] [Full Text]