Cyclic peptides and peptide-like drugs have gained attention in recent years. They are more resistant to metabolic cleavage and bind tighter and are more potent compared to linear peptides. It was shown in recent years that on bead cyclization results in a lower number of byproducts due to more conformational restriction and protection of the C-terminal carboxyl group of the peptide compared to the off-bead peptide. The on-bead   In order to develop cyclic peptide libraries for future screening against oncogenic proteins, we are investigating the efficiencies and mechanisms of on-resin cyclization reactions such as Copper catalyzed Azide-Alkyne Cycloaddition (CuAAC) reaction. We will present our findings on variations observed by changing parameters like resin loading, peptide sequence, identity and orientation of azide and alkyne containing amino acids, and effect of terminal functional groups.  Analysis and optimization of these parameters will allow development of on-resin cyclic libraries with monomeric peptides formed thorough intramolecular CuAAC reaction, as opposed to dimeric or polymeric peptides formed through intermolecular CuAAC reaction. Small monomeric cyclic peptides represent a class of peptides which have potential to act as inhibitors of intracellular protein-protein interactions (PPI), whose masses lie between small molecules and larger helical macrocyclic peptides that have been explored as PPI inhibitors.  <br/>

Investigation of on-resin reactions for cyclization efficiency to control monomer / dimer ratios for comprehensive macrocyclic peptide libraries

256th National Meeting (2018)

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