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.
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.
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.
Yan-Li
YL
Song
Jinzhi
J
Tan
Xiao-Min
XM
Luo
Ya-Qiu
YQ
Long
D040761:Biomimetic Materials / Q000138:chemical synthesis / Q000737:chemistry* / Q000145:classification / Q000494:pharmacology; D032701:Biomimetics; D051380:GRB2 Adaptor Protein / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D008024:Ligands; D015394:Molecular Structure; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D010766:Phosphorylation; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000737:chemistry*; D018909:src Homology Domains
D051380:GRB2 Adaptor Protein; D008024:Ligands; D010456:Peptides, Cyclic; D014443:Tyrosine