Reverse thioether ligation route to multimeric peptide antigens.

Area of Science:

• Bioconjugation Chemistry
• Immunology
• Dendrimer Synthesis

Background:

• Multiple antigenic peptide (MAP) dendrimers enhance peptide immunogenicity by displaying multiple epitope copies.
• Conventional MAP synthesis involves linking peptides to a lysine core, achievable in solution or solid phase.
• Existing methods can face challenges with byproduct formation and reagent stability.

Purpose of the Study:

• To develop a reverse approach for synthesizing peptide dendrimers.
• To create a more efficient and cleaner method for conjugating peptides to lysine dendron cores.
• To optimize solid-phase synthesis of thiol-functionalized dendrons for peptide conjugation.

Main Methods:

• Utilizing a convergent synthesis strategy by tethering chloroacetyl-derivatized peptides to thiol-functionalized lysine dendron cores.
• Employing tris(2-carboxyethyl)phosphine (TCEP) for in situ reduction of disulfide bonds, maintaining thiol reactivity.
• Developing an optimized solid-phase procedure to generate tetrathiol dendrons from lysine cores.

Main Results:

• Successful synthesis of peptide dendrimers using the reverse conjugation approach in both solution and solid phase.
• Demonstrated minimal byproduct formation due to controlled TCEP usage, preserving chloroacetyl groups.
• Achieved cleaner peptide-dendrimer products compared to conventional methods.

Conclusions:

• The developed method offers an advantageous alternative for peptide dendrimer synthesis.
• This approach enhances efficiency and product purity in creating multimeric peptide structures.
• The findings contribute to improved strategies for developing peptide-based immunogens and vaccines.