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Introduction <p>Human T-cell leukemia virus type 1 (HTLV-1) infection is initiated by interactions with its envelope glycoprotein surface unit (SU) and three host receptors [glucose transporter type 1, heparan sulfate proteoglycans, and neuropilin-1 (Nrp1)]. A peptide consisting of residues 90–94 (KKPNR) of HTLV-1 SU (SU90–94) reportedly binds to a b1 domain of Nrp1 (Nrp1 b1) and can inhibit the HTLV-1 entry and infection. Our previous results suggested that the last (C-terminal) and second-to-last (93rd) residues of a SU peptide (residues 85–94) affect the Nrp1 b1 binding affinity. Therefore, we expected if SU variant peptides with substitutions at position 93 and/or 94 can bind to Nrp1 b1 stronger than SU90–94 or the SU wild-type peptide (SU-WT), they will become novel inhibitor candidates for blocking HTLV-1 entry targeting Nrp1 b1.</p> Material and Methods <p>In this study, we explored SU variant peptides that can achieve the strongest binding to Nrp1 b1 by glutathione <i>S</i>-transferase (GST) pull-down assay and isothermal titration calorimetry (ITC) experiment. We further characterized its interaction with Nrp1 b1 by nuclear magnetic resonance (NMR), mutagenesis, and in silico simulation experiments.</p> Results <p>The SU-N93P peptide shows the strongest binding to Nrp1 b1 and binds to Nrp1 b1 six-fold as strong as SU-WT does. Moreover, SU-N93P binds to the same SU peptide-binding surface of Nrp1 b1, thereby having a capability of blocking the HTLV-1 SU-Nrp1 interaction.</p> Conclusion <p>Our results suggested that SU-N93P would be a better inhibitor candidate as a starting point toward the fight against the HTLV-1 entry and infection.</p>

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Biophysical Characterization of the Interaction Between Neuropilin-1 b1 Domain and an N93P Peptide from Human T-Cell Leukemia Virus Type 1 Envelope Glycoprotein Surface Unit

  • 期刊论文

  • 发表日期：

    2025年3月4日

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  • Hideki Kusunoki,
  • Chinatsu Ohshima,
  • Toshiyuki Tanaka,
  • Isao Hamaguchi,
  • Shigetarou Mori

摘要

Introduction

Human T-cell leukemia virus type 1 (HTLV-1) infection is initiated by interactions with its envelope glycoprotein surface unit (SU) and three host receptors [glucose transporter type 1, heparan sulfate proteoglycans, and neuropilin-1 (Nrp1)]. A peptide consisting of residues 90–94 (KKPNR) of HTLV-1 SU (SU90–94) reportedly binds to a b1 domain of Nrp1 (Nrp1 b1) and can inhibit the HTLV-1 entry and infection. Our previous results suggested that the last (C-terminal) and second-to-last (93rd) residues of a SU peptide (residues 85–94) affect the Nrp1 b1 binding affinity. Therefore, we expected if SU variant peptides with substitutions at position 93 and/or 94 can bind to Nrp1 b1 stronger than SU90–94 or the SU wild-type peptide (SU-WT), they will become novel inhibitor candidates for blocking HTLV-1 entry targeting Nrp1 b1.

Material and Methods

In this study, we explored SU variant peptides that can achieve the strongest binding to Nrp1 b1 by glutathione S-transferase (GST) pull-down assay and isothermal titration calorimetry (ITC) experiment. We further characterized its interaction with Nrp1 b1 by nuclear magnetic resonance (NMR), mutagenesis, and in silico simulation experiments.

Results

The SU-N93P peptide shows the strongest binding to Nrp1 b1 and binds to Nrp1 b1 six-fold as strong as SU-WT does. Moreover, SU-N93P binds to the same SU peptide-binding surface of Nrp1 b1, thereby having a capability of blocking the HTLV-1 SU-Nrp1 interaction.

Conclusion

Our results suggested that SU-N93P would be a better inhibitor candidate as a starting point toward the fight against the HTLV-1 entry and infection.