Structure-based design and optimization of cyclic peptide ligands targeting delta-like ligand 3

Abstract

Delta-like ligand 3 (DLL3) is a promising theranostic target due to its high and specific overexpression in small cell lung cancer and other neuroendocrine tumors. To develop novel targeting agents, we designed and synthesized a series of cyclic peptides targeting DLL3. We optimized three key residues: Trp9 and Gly4 on the PepSP1171 core scaffold, and Val4 on PepSP1214, through systematic amino acid substitution and incorporation of non-natural residues. This approach yielded six high-affinity peptides with dissociation constants (K_D) below 100 nM and established an initial structure–activity relationship. The most significant improvement was achieved by substituting Val4 with rigid 1-aminocyclopropanecarboxylic acid, which produced the lead peptide B5 with a K_D of 12.3 nM. These results validate our rational design strategy and identify peptide B5 as a promising candidate for the future development of DLL3-targeted theranostic agents.