Nonhelical leash and alpha-helical structures determine the potency of a peptide antagonist of human T-cell leukemia virus entry.
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.
Mirsaliotis
Antonis
A
The Biomedical Research Centre, Ninewells, Hospital and Medical School, The University, Dundee DD1 9SY, Scotland, United Kingdom.
Lamb
Daniel
D
Brighty
David W
DW
D019943:Amino Acid Substitution; D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology*; D002460:Cell Line; D015726:Giant Cells / Q000821:virology; D015368:Human T-lymphotropic virus 1 / Q000254:growth & development*; D006801:Humans; D008958:Models, Molecular; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D017384:Sequence Deletion; D014760:Viral Fusion Proteins / Q000037:antagonists & inhibitors; D053586:Virus Internalization
D000998:Antiviral Agents; D010455:Peptides; D014760:Viral Fusion Proteins