Disulfide-Linked Peptides for Blocking BTLA/HVEM Binding.

Area of Science:

• Immunology
• Molecular Biology
• Structural Biology

Background:

• Immune checkpoints regulate antitumor immune responses through receptor-ligand interactions.
• B- and T-lymphocyte attenuator (BTLA) is a receptor on T-cells that interacts with herpes virus entry mediator (HVEM) on tumor cells.
• HVEM binding to BTLA inhibits T-cell responses, representing a target for cancer immunotherapy.

Purpose of the Study:

• To investigate the molecular interaction between BTLA and HVEM.
• To develop novel inhibitors targeting the BTLA/HVEM interaction for cancer immunotherapy.

Main Methods:

• Utilized the crystal structure of the BTLA/HVEM complex.
• Employed molecular modeling to design inhibitors of the BTLA/HVEM interaction.
• Synthesized novel compounds and assessed their ability to inhibit BTLA/HVEM complex formation.

Main Results:

• Identified that BTLA binds to the N-terminal cysteine-rich domain of HVEM.
• Developed and synthesized novel compounds capable of interacting with BTLA.
• The HVEM (14-39) peptide demonstrated potent inhibition of BTLA/HVEM complex formation.

Conclusions:

• The HVEM (14-39) peptide is a promising inhibitor of the BTLA/HVEM interaction.
• Targeting the BTLA/HVEM pathway with novel inhibitors represents a viable strategy for cancer immunotherapy.