Design, Synthesis, Biological Activity, and Structural Analysis of Lactam‐Constrained PTPRJ Agonist Peptides

PTPRJ is a receptor‐like protein tyrosine phosphatase mainly known for its antiproliferative and tumor‐suppressive functions. PTPRJ dephosphorylates several growth factors and their receptors, negatively regulating cell proliferation and migration. We recently identified a disulfide‐bridged nonapeptide, named PTPRJ‐19 (H‐[Cys‐His‐His‐Asn‐Leu‐Thr‐His‐Ala‐Cys]‐OH), which activates PTPRJ, thereby causing cell growth inhibition and apoptosis of both cancer and endothelial cells. With the aim of replacing the disulfide bridge by a chemically more stable moiety, we have synthesized and tested a series of lactam analogues of PTPRJ‐19. This replacement led to analogues with higher activity and greater stability than the parent peptide. Disulfide vs. lactam: This work focused on the design and biological evaluation of PTPRJ agonist peptides. Derivatives of PTPRJ‐19 were generated by replacing the disulfide bridge chain with a lactam bridge. Our study provided a new derivative, peptide 7, with better anticancer cell growth activity and improved stability under various conditions.