Advancements in loop cyclisation approaches for enhanced pep1de therapeutics for targeting protein-protein interactions

Protein-protein interactions (PPIs) are pivotal in regulating cellular functions and life processes, making them promising therapeutic targets in modern medicine. Despite their potential, developing PPI inhibitors poses significant challenges due to their large and shallow interfaces that complicate ligand binding. This study focuses on mimicking peptide loops as a strategy for PPI inhibition, utilising synthetic peptide loops for replicating critical binding regions. This current work explores turn-inducing elements and highlights the importance of proline in promoting favourable conformations for lactamisation, yielding high-purity cyclic peptides. Notably, our one-pot method offers enhanced versatility and represents a robust strategy for efficient and selective macrolactamisation, expanding the scope of peptide synthesis methodologies. This approach, validated through the synthesis of AAV capsid-derived loops, offers a robust platform for developing peptide-based therapeutics and highlights the potential of peptide macrocycles in overcoming PPI drug discovery challenges and advancing new therapeutics development.