Multimerization of an apoptogenic TRAIL-mimicking peptide by using adamantane-based dendrons

Area of Science:

• Biochemistry
• Molecular Biology
• Drug Discovery

Background:

• The natural tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) plays a role in programmed cell death.
• Multivalency is crucial for effective ligand-receptor interactions in biological systems.
• Developing synthetic ligands that mimic TRAIL's function is a key area in cancer therapy research.

Purpose of the Study:

• To create multivalent forms of an apoptogenic peptide using adamantane-based dendrons.
• To investigate the impact of peptide multivalency on binding affinity to TRAIL receptor 2 (TR2).
• To assess the efficacy of multivalent peptides in inducing apoptosis in TR2-expressing cells.

Main Methods:

• Synthesis of adamantane-based dendrons as multivalent scaffolds.
• Peptide multimerization using the dendron scaffolds.
• Surface plasmon resonance (SPR) to measure binding affinity to TR2.
• In vitro cell death assays using BJAB cells expressing TR2.

Main Results:

• Trimeric and hexameric peptide forms showed significantly increased binding affinity to TR2 (1500-fold and 20,000-fold, respectively) compared to the monomer.
• Only multimeric peptides (trimeric and hexameric) induced significant cell death in TR2-expressing BJAB cells.
• These findings confirm the necessity of a multivalent structure for effective TR2-dependent apoptosis induction.

Conclusions:

• Adamantane-based dendrons provide an effective scaffold for creating multivalent apoptogenic peptides.
• Multivalency dramatically enhances peptide affinity and apoptotic activity towards TR2.
• This approach offers valuable insights into ligand-receptor interactions and potential therapeutic strategies targeting TRAIL pathways.