Cyclic phosphopeptides for interference with Grb2 SH2 domain signal transduction prepared by ring-closing metathesis and phosphorylation.

Cyclic phosphopeptides were prepared using ring-closing metathesis followed by phosphorylation. These cyclic phosphopeptides were designed to interact with the SH2 domain of Grb2, which is a signal transduction protein of importance as a target for antiproliferative drug development. Binding of these peptides to the Grb2 SH2 domain was evaluated by a surface plasmon resonance assay. High affinity binding to the Grb2 SH2 domain was maintained upon macrocyclization, thus indicating that this method can be used to assemble high affinity cyclic phosphopeptides that interfere with signal transduction cascades.

[1]  Dajun Yang,et al.  Utilization of a beta-aminophosphotyrosyl mimetic in the design and synthesis of macrocyclic Grb2 SH2 domain-binding peptides. , 2003, Journal of medicinal chemistry.

[2]  J. Iqbal,et al.  Synthesis of a novel cis-proline-derived cyclic type VI beta-turn mimic via ring-closing metathesis. , 2003, The Journal of organic chemistry.

[3]  R. Liskamp,et al.  Role of solution conformation and flexibility of short peptide ligands that bind to the p56(lck) SH2 domain. , 2003, Bioorganic & medicinal chemistry.

[4]  Thomas B. Sundberg,et al.  Design and synthesis of conformationally constrained, extended and reverse turn pseudopeptides as Grb2-SH2 domain antagonists , 2003 .

[5]  Dajun Yang,et al.  Macrocyclization in the design of Grb2 SH2 domain-binding ligands exhibiting high potency in whole-cell systems. , 2003, Journal of medicinal chemistry.

[6]  Jean Martínez,et al.  Cyclic RGD peptide by ring-closing metathesis , 2002 .

[7]  Malcolm B. Gillies,et al.  Experimental and calculated shift in pK(a) upon binding of phosphotyrosine peptide to the SH2 domain of p56(lck). , 2002, Bioorganic & medicinal chemistry.

[8]  Wendell A Lim,et al.  The modular logic of signaling proteins: building allosteric switches from simple binding domains. , 2002, Current opinion in structural biology.

[9]  Gabriel Waksman,et al.  Calorimetric and structural studies of 1,2,3-trisubstituted cyclopropanes as conformationally constrained peptide inhibitors of Src SH2 domain binding. , 2002, Journal of the American Chemical Society.

[10]  T. Burke,et al.  Macrocyclization in the design of a conformationally constrained Grb2 SH2 domain inhibitor. , 2001, Bioorganic & medicinal chemistry letters.

[11]  R. Liskamp,et al.  Synthesis of cyclic peptides by ring-closing metathesis. , 2000, The Journal of organic chemistry.

[12]  G. Verdine,et al.  An All-Hydrocarbon Cross-Linking System for Enhancing the Helicity and Metabolic Stability of Peptides , 2000 .

[13]  Reichwein,et al.  Rolling Loop Scan: An Approach Featuring Ring-Closing Metathesis for Generating Libraries of Peptides with Molecular Shapes Mimicking Bioactive Conformations or Local Folding of Peptides and Proteins. , 1999, Angewandte Chemie.

[14]  Scott J. Miller,et al.  A Biomimetic Approach to Asymmetric Acyl Transfer Catalysis , 1999 .

[15]  P. Ettmayer,et al.  Structural and conformational requirements for high-affinity binding to the SH2 domain of Grb2(1). , 1999, Journal of medicinal chemistry.

[16]  Tony Pawson,et al.  Mammalian Grb2 Regulates Multiple Steps in Embryonic Development and Malignant Transformation , 1998, Cell.

[17]  Scott J. Miller,et al.  Application of Ring-Closing Metathesis to the Synthesis of Rigidified Amino Acids and Peptides , 1996 .

[18]  Scott J. Miller,et al.  Synthesis of Conformationally Restricted Amino Acids and Peptides Employing Olefin Metathesis , 1995 .

[19]  C. Steel,et al.  Solvent Reorganization and Thermodynamic Enthalpy-Entropy Compensation , 1995 .

[20]  Tony Pawson,et al.  Protein modules and signalling networks , 1995, Nature.

[21]  K. Blumer,et al.  Association of p62, a multifunctional SH2- and SH3-domain-binding protein, with src family tyrosine kinases, Grb2, and phospholipase C gamma-1 , 1995, Molecular and cellular biology.

[22]  Thomas Kolter,et al.  Peptidomimetics for Receptor Ligands—Discovery, Development, and Medical Perspectives , 1993 .

[23]  A. Ullrich,et al.  The SH2 and SH3 domain-containing protein GRB2 links receptor tyrosine kinases to ras signaling , 1992, Cell.

[24]  T Pawson,et al.  SH2 and SH3 domains: elements that control interactions of cytoplasmic signaling proteins. , 1991, Science.

[25]  E. V. Arx,et al.  Das 4,4′-tetramethyldiamino-diphenylmethan reagens (TDM) , 1976 .

[26]  J. H. Boom,et al.  N, N‐diisopropyl‐bis(4‐chlorobenzyl) phosphoramidite: A versatile phosphitylating agent for the phosphorylation of hydroxy amino acids and preparation of protected phosphopeptides , 1990 .

[27]  P. Sieber.  An improved method for anchoring of 9-fluorenylmethoxycarbonyl-amino acids to 4-alkoxybenzyl alcohol resins. , 1987 .