Synthesis and Optimization of Stapled DOCK Peptides with Improved Drug-like Properties

Abstract

Protein-protein interactions (PPIs) involving short α -helix fragments are of critical importance in cellular processes. Stapling of α -helical peptides improves their conformational stability, affinity, and resistance to proteases. ELMO proteins (ELMO1 and ELMO2) play a crucial role in cellular processes, and recent studies highlight ELMO1's distinct role in interacting with, and modulating, DOCK2 levels. To harness the full therapeutic potential of peptides mimicking the DOCK protein for interference with the ELMO/DOCK interaction, we propose employing deoxycholic acid and conventional small molecules for stapling, thus enhancing the therapeutic potential of these peptides. Our method employs solid-phase peptide synthesis, strategically incorporating two cysteine amino acids to create well-defined, constrained cyclic peptides upon stapling. In addition to their structural stabilisation, these stapled peptides exhibit remarkable proteolytic stability, defying enzymatic degradation, even in the presence of human serum.