title: Synthesis and evaluation of conformationally constrained peptide analogues as the Src SH3 domain binding ligands.
abstract: Src kinase activity is regulated by the interaction of SH3 domain with protein sequences that are rich in proline residues. Identification of more potent SH3 domain binding ligands that can regulate Src kinase activity is a subject of major interest. Conformationally constrained peptides have been previously used for improving the binding potency of the Src SH2 domain binding peptide ligands and peptide substrates of the substrate-binding site of Src. A series of peptide analogues of Ac-VSLARRPLPPLP (1, Ac-VSL12, Kd=0.34 microM) were synthesized by introducing conformational constraints to improve the binding affinity towards the Src SH3 domain. Peptides synthesized through cyclization between N-terminal to C-terminal [VSLARRPLPPLP] or N-terminal to side chain flanking residues (i.e., [(beta)AVS]LARRPLPPLP and [VSLE]RRPLPPLP) exhibited at least 6.4-fold less binding affinity (Kd=2.19-4.85 microM) when compared to 1. The data suggest upon N-terminal cyclization with C-terminal or flanking residues, the interactions of the amino acids in the core RPLPPLP reduce significantly with the residues within the Src SH3 domain. Conformationally constrained peptide V[SLARRPLPPLP] (5) was synthesized through cyclization of C-terminal to the serine side chain and displayed a comparable binding affinity (Kd=0.35 microM) towards the Src SH3 domain versus that of 1. Thus, this template may be used to optimize and generate more potent analogues with higher stability.
authors.affiliation: Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, 41 Lower College Road, Kingston, RI 02881, USA.
authors.forename: Rakesh
authors.initials: R
authors.lastname: Tiwari
authors.forename: Alex
authors.initials: A
authors.lastname: Brown
authors.forename: Seetha
authors.initials: S
authors.lastname: Narramaneni
authors.forename: Gongqin
authors.initials: G
authors.lastname: Sun
authors.forename: Keykavous
authors.initials: K
authors.lastname: Parang
mesh_terms: D004591:Electrophoresis, Polyacrylamide Gel; D005454:Fluorescence Polarization; D008024:Ligands; D015394:Molecular Structure; D010455:Peptides / Q000138:chemical synthesis* / Q000737:chemistry*; D011485:Protein Binding; D018909:src Homology Domains
chemical_list: D008024:Ligands; D010455:Peptides