title: Structure-based design of thioether-bridged cyclic phosphopeptides binding to Grb2-SH2 domain.
abstract: A series of phosphotyrosine containing cyclic peptides was designed and synthesized based upon the phage library derived cyclopeptide, G1TE. Considering the type-I beta-turn feature of peptidic ligand binding to Grb2 SH2 domain, we introduce alpha,alpha-disubstituted cyclic amino acid, Ach, into the 4th position of the cyclic peptide to induce a local right handed 3(10) helical conformation. In order to stabilize the favorable binding conformation, the bulky and hydrophobic amino acids, neopentylglycine (NPG) and phenylalanine, were introduced into the 8th and 2nd positions of the peptide ligand, respectively. To facilitate the sidechain of pTyr3 reaching into the phosphotyrosine binding pocket, a less bulky alanine was preferred in position 1. Based upon these global modifications, a highly potent peptide ligand 12 was discovered with an IC(50)=1.68 nM, evaluated by ELISA binding essay. Ligand 12 is at least 10(5) more potent than the lead peptide, termed G1TE.
authors.affiliation: Laboratory of Medicinal Chemistry, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA.
authors.forename: Peng
authors.initials: P
authors.lastname: Li
authors.forename: Megan L
authors.initials: ML
authors.lastname: Peach
authors.forename: Manchao
authors.initials: M
authors.lastname: Zhang
authors.forename: Hongpeng
authors.initials: H
authors.lastname: Liu
authors.forename: Dajun
authors.initials: D
authors.lastname: Yang
authors.forename: Marc
authors.initials: M
authors.lastname: Nicklaus
authors.forename: Peter P
authors.initials: PP
authors.lastname: Roller
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000596:Amino Acids / Q000737:chemistry; D001665:Binding Sites; D003500:Cyclization; D015195:Drug Design; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D051380:GRB2 Adaptor Protein; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D008968:Molecular Conformation; D010456:Peptides, Cyclic / Q000737:chemistry* / Q000378:metabolism*; D010748:Phosphopeptides / Q000737:chemistry* / Q000378:metabolism*; D019000:Phosphotyrosine / Q000737:chemistry; D011485:Protein Binding; D017433:Protein Structure, Secondary; D011506:Proteins / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013440:Sulfides / Q000737:chemistry*; D018909:src Homology Domains
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000596:Amino Acids; D051380:GRB2 Adaptor Protein; D010456:Peptides, Cyclic; D010748:Phosphopeptides; D011506:Proteins; D013440:Sulfides; D019000:Phosphotyrosine