CD160-Derived Peptide as a Bidirectional Inhibitor Toward Immune Checkpoints BTLA/HVEM and HVEM/LIGHT
Magdalena Lipińska1, Piotr Ciura1, Simon Gumpelmair2
1Faculty of Chemistry, University of Gdańsk, Wita Stwosza 63, 80-308 Gdańsk, Poland.
Insights
Researchers developed peptide inhibitors targeting immune checkpoints. Peptide A5 effectively blocks BTLA/HVEM and HVEM/LIGHT interactions, showing potential for treating immune disorders.
Area of Science:
- Immunology
- Molecular Biology
- Drug Discovery
Background:
- Immune checkpoints like BTLA and HVEM regulate immune responses.
- HVEM interacts with both BTLA and CD160, making it a potential therapeutic target.
- Targeting the overlapping binding sites could yield novel inhibitors.
Purpose of the Study:
- To design and evaluate peptide inhibitors targeting the HVEM binding interface.
- To identify peptides that can disrupt BTLA/HVEM and potentially other HVEM interactions.
- To explore the therapeutic potential of these inhibitors for immune-related disorders.
Main Methods:
- Peptide synthesis based on CD160-derived fragments.
- Surface Plasmon Resonance (SpS) analysis for HVEM binding affinity.
- Enzyme-Linked Immunosorbent Assay (ELISA) and cell-based assays for inhibitory activity.
- Molecular docking simulations to predict binding modes.
Main Results:
- Peptide A5 demonstrated significant binding to HVEM.
- A5 effectively inhibited the BTLA/HVEM interaction.
- Molecular docking indicated A5 binds to HVEM at both BTLA and LIGHT interaction sites.
- ELISA and cell-based assays confirmed A5 disrupts BTLA/HVEM and HVEM/LIGHT complex formation.
Conclusions:
- Peptide A5 acts as a dual inhibitor of HVEM interactions.
- A5 shows promise as a therapeutic agent for immune-related disorders.
- Targeting HVEM interactions offers a novel strategy for immune modulation.
Abstract:
BTLA and HVEM are key immune checkpoint proteins involved in regulating immune responses. Since HVEM also binds to CD160 at a site that overlaps with the BTLA binding site, CD160-derived fragments were used to design peptide inhibitors targeting this interface. Several peptides were synthesized and assessed for HVEM binding using SpS analysis, and their inhibitory activity was evaluated in ELISA and cell-based assays. One peptide, namely A5, demonstrated strong HVEM binding and effectively blocked the BTLA/HVEM interaction. Molecular docking results revealed that peptide A5 binds to HVEM not only at the BTLA interaction site but also at the region involved in LIGHT binding. Consistent with these findings, ELISA and cell-based assays confirmed that A5 effectively disrupts both BTLA/HVEM and HVEM/LIGHT complex formation. These results suggest that A5 acts as a dual inhibitor of HVEM interactions, with potential therapeutic implications for immune-related disorders.
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