Discovery of thioether-bridged cyclic pentapeptides binding to Grb2-SH2 domain with high affinity.
Blocking the interaction between phosphotyrosine (pTyr)-containing activated receptors and the Src homology 2 (SH2) domain of the growth factor receptor-bound protein 2 (Grb 2) is considered to be an effective and non-cytotoxic strategy to develop new anti-proliferate agents due to its potential to shut down the Ras activation pathway. In this study, a series of phosphotyrosine containing cyclic pentapeptides were designed and synthesized based upon the phage library derived cyclopeptide, G1TE. A comprehensive SAR study was also carried out to develop potent Grb2-SH2 domain antagonists based upon this novel template. With both the peptidomimetic optimization of the amino acid side-chains and the constraint of the backbone conformation guided by molecular modeling, we developed several potent antagonists with low micromolar range binding affinity, such as cyclic peptide 15 with an K(d)=0.359microM, which is providing a novel template for the development of Grb2-SH2 domain antagonists as potential therapeutics for certain cancers.
Jiang
Sheng
S
Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, PR China. jiang_sheng@gibh.ac.cn
Liao
Chenzhong
C
Bindu
Lakshman
L
Yin
Biaolin
B
Worthy
Karen W
KW
Fisher
Robert J
RJ
Burke
Terrence R
TR
Nicklaus
Marc C
MC
Roller
Peter P
PP
D000595:Amino Acid Sequence; D003198:Computer Simulation; D055808:Drug Discovery; D051380:GRB2 Adaptor Protein / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019151:Peptide Library; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000737:chemistry*; D011485:Protein Binding; D013329:Structure-Activity Relationship; D018909:src Homology Domains
C403002:G1TE cyclic peptide; D051380:GRB2 Adaptor Protein; D019151:Peptide Library; D010456:Peptides, Cyclic