title: Design and characterization of non-phosphopeptide inhibitors for Src family SH2 domains.
abstract: The development of novel non-phosphopeptide inhibitors for the Src family SH2 domain is described. Several commercially available hydroxyl aromatic acids have been appended off the N-terminus of pYEEIE and the potent phosphopeptide inhibitors of GST-Lck-SH2 were identified via ELISA. The most potent inhibitor, caffeic acid-pYEEIE, exhibited approximately 30-fold more binding activity than Ac-pYEEIE. Non-phosphopeptides were synthesized by replacing phosphotyrosine of caffeic acid-pYEEIE with tyrosine or 3,4-dihydroxyphenylalanine (DOPA). Caffeic acid-DOPA-EEIE that did not contain phosphotyrosine and its isosteres exhibited less than 20 times decreased binding affinity for GST-Lck-SH2 than Ac-pYEEIE. Moreover, it had a similar binding affinity for the GST-Lck-SH2, GST-Src-SH2, and GST-Fyn-SH2 domains. This study showed that the pY-1 positions of the phosphopeptide inhibitors and of the non-phosphopeptide inhibitors played an important role in the binding for the SH2 domain and that the non-phosphopeptide inhibitor must be a new lead in the development of SH2 inhibitors.
authors.affiliation: Signal Transduction Laboratory, Mogam Biotechnology Research Institute, 341 Pojung-Ri, Koosung-Myun, Yongin-City, Kyunggi-Do, South Korea.
authors.forename: See-Hyoung
authors.initials: SH
authors.lastname: Park
authors.forename: Jonghwa
authors.initials: J
authors.lastname: Won
authors.forename: Keun-Hyeung
authors.initials: KH
authors.lastname: Lee
mesh_terms: D002109:Caffeic Acids / Q000138:chemical synthesis* / Q000494:pharmacology*; D004295:Dihydroxyphenylalanine / Q000737:chemistry; D004797:Enzyme-Linked Immunosorbent Assay; D016391:Genes, src / Q000187:drug effects*; D010455:Peptides / Q000138:chemical synthesis* / Q000494:pharmacology*; D019000:Phosphotyrosine / Q000737:chemistry; D014443:Tyrosine / Q000737:chemistry; D018909:src Homology Domains / Q000187:drug effects*
chemical_list: D002109:Caffeic Acids; D010455:Peptides; D019000:Phosphotyrosine; D014443:Tyrosine; D004295:Dihydroxyphenylalanine