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Peptide Scanning-assisted Identification of a Monoclonal Antibody-recognized Linear B-cell Epitope
Published on: March 24, 2017
An antiviral peptide targets a coiled-coil domain of the human T-cell leukemia virus envelope glycoprotein
Josefina D Piñón1, Sharon M Kelly, Nicholas C Price
1The Biomedical Research Centre, Ninewells Hospital and Medical School, The University, Dundee DD1 9SY, United Kingdom.
Abstract:
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.
Insights
Synthetic peptides inhibit human T-cell leukemia virus type 1 (HTLV-1) entry by targeting its envelope fusion structure. These peptides disrupt a key protein formation, offering potential therapeutic strategies for HTLV-1 infections.
Area of Science:
- Virology
- Molecular Biology
- Structural Biology
Background:
- Retrovirus entry into host cells depends on viral envelope glycoproteins mediating membrane fusion.
- Human T-cell leukemia virus type 1 (HTLV-1) entry can be inhibited by synthetic peptides mimicking its transmembrane glycoprotein (TM).
Purpose of the Study:
- To investigate the mechanism by which HTLV-1 TM-derived peptides inhibit viral entry.
- To identify the specific target structure of these inhibitory peptides on the HTLV-1 envelope.
- To explore the potential therapeutic applications of these peptides.
Main Methods:
- Utilized synthetic peptides based on the HTLV-1 TM ectodomain.
- Performed binding assays to determine peptide interaction with viral envelope structures.
- Analyzed the effect of peptide binding on the formation of fusion-essential protein structures.
Main Results:
- The inhibitory peptides specifically bind to a core coiled-coil domain within the HTLV-1 envelope.
- Peptide variants lacking binding to the coiled-coil domain did not inhibit viral entry.
- Data suggest peptides disrupt the formation of the trimer-of-hairpins structure required for membrane fusion.
- Enhanced potency peptides were successfully generated.
Conclusions:
- HTLV-1 inhibitory peptides target a fusion-active coiled-coil structure of the viral envelope.
- Disruption of the trimer-of-hairpins structure is the likely inhibitory mechanism.
- Peptides or mimetics targeting this structure hold therapeutic potential for HTLV-1 infections.
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