Design and Synthesis of Potent Bivalent Peptide Agonists Targeting the EphA2 Receptor
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- 作者：Srinivas Duggineni ; Sayantan Mitra ; Ilaria Lamberto ; Xiaofeng Han ; Yan Xu ; Jing An ; Elena B. Pasquale ; Ziwei Huang
- 刊名：ACS Medicinal Chemistry Letters
- 出版年：2013
- 出版时间：March 14, 2013
- 年：2013
- 卷：4
- 期：3
- 页码：344-348
- 全文大小：317K
- 年卷期：v.4,no.3(March 14, 2013)
- ISSN：1948-5875
文摘
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鈥揳ctivity 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 six-carbon linker, has about 13-fold increased potency as compared to SWL. Furthermore, similar to SWL, the dimeric peptide is an agonist and can promote EphA2 tyrosine phosphorylation (activation) in cultured cells.