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Utilization of 3'-carboxy-containing tyrosine derivatives as a new class of phosphotyrosyl mimetics in the preparation of novel non-phosphorylated cyclic peptide inhibitors of the Grb2-SH2 domain. 2006

Yan-Li Song, and Jinzhi Tan, and Xiao-Min Luo, and Ya-Qiu Long
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Graduate School of the Chinese Academy of Sciences, CAS, 555 Zuchongzhi Road, Shanghai, 201203, China.

A new class of phosphotyrosyl (pTyr) mimetics, distinct from the conventional pTyr mimetic design of adding non-hydrolyzable acidic functionalities to the 4'-position of phenylalanine, was created by introducing carboxy-containing groups to the 3'-position of tyrosine. The effect of the chain length of the carboxy substituent was examined. Reported herein is the chiral pool synthesis of the new pTyr mimetics, and their first use in a novel non-phosphorylated Grb2-SH2 domain binding motif with the 5-amino-acid sequence Xx1-Leu-(3'-substituted-Tyr)-Ac6c-Asn. The highest affinity was exhibited by the 3-L-(2-carboxyethyl)tyrosine-containing sulfoxide-cyclized peptide , with an IC50 = 1.1 microM, providing a promising new template for further development of potent Grb2-SH2 domain inhibitors with reduced charge and peptidic nature, but improved selectivity and bioavailability.

UI MeSH Term Description Entries
D008024 Ligands A molecule that binds to another molecule, used especially to refer to a small molecule that binds specifically to a larger molecule, e.g., an antigen binding to an antibody, a hormone or neurotransmitter binding to a receptor, or a substrate or allosteric effector binding to an enzyme. Ligands are also molecules that donate or accept a pair of electrons to form a coordinate covalent bond with the central metal atom of a coordination complex. (From Dorland, 27th ed) Ligand
D010456 Peptides, Cyclic Peptides whose amino acid residues are linked together forming a circular chain. Some of them are ANTI-INFECTIVE AGENTS; some are biosynthesized non-ribosomally (PEPTIDE BIOSYNTHESIS, NON-RIBOSOMAL). Circular Peptide,Cyclic Peptide,Cyclic Peptides,Cyclopeptide,Orbitide,Circular Peptides,Cyclopeptides,Orbitides,Peptide, Circular,Peptide, Cyclic,Peptides, Circular
D010766 Phosphorylation The introduction of a phosphoryl group into a compound through the formation of an ester bond between the compound and a phosphorus moiety. Phosphorylations
D014443 Tyrosine A non-essential amino acid. In animals it is synthesized from PHENYLALANINE. It is also the precursor of EPINEPHRINE; THYROID HORMONES; and melanin. L-Tyrosine,Tyrosine, L-isomer,para-Tyrosine,L Tyrosine,Tyrosine, L isomer,para Tyrosine
D015394 Molecular Structure The location of the atoms, groups or ions relative to one another in a molecule, as well as the number, type and location of covalent bonds. Structure, Molecular,Molecular Structures,Structures, Molecular
D051380 GRB2 Adaptor Protein A signal transducing adaptor protein that links extracellular signals to the MAP KINASE SIGNALING SYSTEM. Grb2 associates with activated EPIDERMAL GROWTH FACTOR RECEPTOR and PLATELET-DERIVED GROWTH FACTOR RECEPTORS via its SH2 DOMAIN. It also binds to and translocates the SON OF SEVENLESS PROTEINS through its SH3 DOMAINS to activate PROTO-ONCOGENE PROTEIN P21(RAS). Growth Factor Receptor-Bound Protein-2,Abundant Src Homology Protein,GRB2 Adaptor Protein, Grb3-3 Isoform,Grb3-3 Adaptor Protein,GRB2 Adaptor Protein, Grb3 3 Isoform,Growth Factor Receptor Bound Protein 2
D018909 src Homology Domains Regions of AMINO ACID SEQUENCE similarity in the SRC-FAMILY TYROSINE KINASES that fold into specific functional tertiary structures. The SH1 domain is a CATALYTIC DOMAIN. SH2 and SH3 domains are protein interaction domains. SH2 usually binds PHOSPHOTYROSINE-containing proteins and SH3 interacts with CYTOSKELETAL PROTEINS. SH Domains,SH1 Domain,SH2 Domain,SH3 Domain,src Homology Region 2 Domain,Homology Domain, src,Homology Domains, src,SH Domain,SH1 Domains,SH2 Domains,SH3 Domains,src Homology Domain
D032701 Biomimetics An interdisciplinary field in materials science, ENGINEERING, and BIOLOGY, studying the use of biological principles for synthesis or fabrication of BIOMIMETIC MATERIALS. Mimetics, Biological,Bio-inspired Engineering,Biomimicry Engineering,Biomimicry Science,Bio inspired Engineering,Bio-inspired Engineerings,Biological Mimetic,Biological Mimetics,Biomimetic,Biomimicry Engineerings,Biomimicry Sciences,Engineering, Bio-inspired,Engineering, Biomimicry,Engineerings, Bio-inspired,Engineerings, Biomimicry,Mimetic, Biological,Science, Biomimicry,Sciences, Biomimicry
D040761 Biomimetic Materials Materials fabricated by BIOMIMETICS techniques, i.e., based on natural processes found in biological systems. Bio-Inspired Devices,Bio-Inspired Materials,Bioinspired Devices,Bioinspired Materials,Biomimetic Devices,Biomimicry Devices,Biomimicry Materials,Bio Inspired Devices,Bio Inspired Materials,Bio-Inspired Device,Bio-Inspired Material,Bioinspired Device,Bioinspired Material,Biomimetic Device,Biomimetic Material,Biomimicry Device,Biomimicry Material,Device, Bio-Inspired,Device, Bioinspired,Device, Biomimetic,Device, Biomimicry,Devices, Bio-Inspired,Devices, Bioinspired,Devices, Biomimetic,Devices, Biomimicry,Material, Bio-Inspired,Material, Bioinspired,Material, Biomimetic,Material, Biomimicry,Materials, Bio-Inspired,Materials, Bioinspired,Materials, Biomimetic,Materials, Biomimicry

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