Accessing diverse bicyclic peptide conformations using 1,2,3-TBMB as a linker

Area of Science:

• Medicinal Chemistry
• Peptide Chemistry
• Drug Discovery

Background:

• Bicyclic peptides are effective for targeting difficult drug targets, including protein-protein interactions.
• Conventional bicyclisation methods often yield limited conformational diversity.

Purpose of the Study:

• To explore the use of 1,2,3-tris(bromomethyl)benzene (1,2,3-TBMB) as a novel linker for creating bicyclic peptides.
• To generate bicyclic peptides with diverse conformations distinct from those produced by 1,3,5-TBMB.
• To assess the efficiency and scope of 1,2,3-TBMB-mediated bicyclisation.

Main Methods:

• Bicyclisation of peptides at cysteine residues using 1,2,3-TBMB under aqueous buffer conditions.
• Testing the reaction's broad substrate scope and compatibility with high-throughput screening.
• Evaluating the conversion efficiency and purity of the resulting bicyclic peptides.

Main Results:

• Efficient bicyclisation was achieved using 1,2,3-TBMB across a broad range of peptide substrates.
• High conversion rates (>90%) were observed for 96 out of 115 tested peptides.
• The method demonstrated compatibility with high-throughput screening and aqueous buffer conditions.
• Generated bicyclic peptides exhibited diverse conformations compared to conventional methods.

Conclusions:

• 1,2,3-TBMB is a versatile linker for synthesizing diverse bicyclic peptides.
• This approach offers an efficient and broadly applicable method for peptide drug discovery.
• The 1,2,3-TBMB linker is suitable for various peptide screening techniques.