Constrained\nβ‑Hairpins Targeting the\nEphA4 Ligand Binding Domain

The activity of the\nreceptor tyrosine kinase EphA4 has\nbeen implicated\nin several pathologies including oncology (gastric and pancreatic\ncancers) and neurodegenerative diseases (amyotrophic lateral sclerosis\nand Alzheimer’s disease). However, advances in validating EphA4\nas a possible drug target have been limited by the lack of suitable\npharmacological inhibitors. Recently, we reported on the design of\npotent EphA4 agonistic agents targeting its ligand binding domain\n(LBD). Based on previous studies with a phage display cyclic peptide\ninhibitor, we designed a β-hairpin mimetic with high affinity\nfor EphA4-LBD. These agents hold great promise for further validation\nand development of EphA4-based therapeutics. Moreover, our studies\nintroduce a possible strategy for the design of constrained β-hairpin\npeptides.