An antiviral peptide targets a coiled-coil domain of the human T-cell leukemia virus envelope glycoprotein.
Retrovirus entry into cells is mediated by the viral envelope glycoproteins which, through a cascade of conformational changes, orchestrate fusion of the viral and cellular membranes. In the absence of membrane fusion, viral entry into the host cell cannot occur. For human T-cell leukemia virus type 1 (HTLV-1), synthetic peptides that mimic a carboxy-terminal region of the transmembrane glycoprotein (TM) ectodomain are potent inhibitors of membrane fusion and virus entry. Here, we demonstrate that this class of inhibitor targets a fusion-active structure of HTLV-1 envelope. In particular, the peptides bind specifically to a core coiled-coil domain of envelope, and peptide variants that fail to bind the coiled-coil lack inhibitory activity. Our data indicate that the inhibitory peptides likely function by disrupting the formation of a trimer-of-hairpins structure that is required for membrane fusion. Importantly, we also show that peptides exhibiting dramatically increased potency can be readily obtained. We suggest that peptides or peptide mimetics targeting the fusion-active structures of envelope may be of therapeutic value in the treatment of HTLV-1 infections.
Piñón
Josefina D
JD
The Biomedical Research Centre, Ninewells Hospital and Medical School, The University, Dundee DD1 9SY, United Kingdom.
Kelly
Sharon M
SM
Price
Nicholas C
NC
Flanagan
Jack U
JU
Brighty
David W
DW
D000595:Amino Acid Sequence; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D002460:Cell Line; D015726:Giant Cells / Q000187:drug effects; D006367:HeLa Cells; D015368:Human T-lymphotropic virus 1 / Q000187:drug effects / Q000472:pathogenicity*; D006801:Humans; D008561:Membrane Fusion / Q000187:drug effects*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D014759:Viral Envelope Proteins / Q000737:chemistry* / Q000187:drug effects* / Q000378:metabolism
D000998:Antiviral Agents; D010455:Peptides; D014759:Viral Envelope Proteins