title: Design and Synthesis of Potent Bivalent Peptide Agonists Targeting the EphA2 Receptor.
abstract: Designing potent and selective peptides and small molecules that target Eph receptor tyrosine kinases remains a challenge and new strategies are needed for developing novel and potent ligands for these receptors. In this study, we performed a structure-activity relationship study of a previously identified 12 amino acid-long peptide, SWL, by alanine scanning to identify residues important for receptor binding. To further enhance and optimize the receptor binding affinity of the SWL peptide, we applied the concept of bivalent ligand design to synthesize several SWL-derived dimeric peptides as novel ligands capable of binding simultaneously to two EphA2 receptor molecules. The dimeric peptides possess higher receptor binding affinity than the original monomeric SWL peptide, consistent with bivalent binding. The most potent dimeric peptide, a SWL dimer with a 6 carbon linker, has about 13 fold increased potency compared to SWL. Furthermore, similar to SWL, the dimeric peptide is an agonist and can promote EphA2 tyrosine phosphorylation (activation) in cultured cells.
authors.affiliation: SUNY Upstate Cancer Research Institute, Department of Pharmacology, State University of New York, Syracuse, New York 13210, USA.
authors.forename: Srinivas
authors.initials: S
authors.lastname: Duggineni
authors.forename: Sayantan
authors.initials: S
authors.lastname: Mitra
authors.forename: Ilaria
authors.initials: I
authors.lastname: Lamberto
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Han
authors.forename: Yan
authors.initials: Y
authors.lastname: Xu
authors.forename: Jing
authors.initials: J
authors.lastname: An
authors.forename: Elena B
authors.initials: EB
authors.lastname: Pasquale
authors.forename: Ziwei
authors.initials: Z
authors.lastname: Huang
keywords: Eph receptors; peptide inhibitors; protein-protein interactions; structure-based drug design