Cyclic peptidyl inhibitors of Grb2 and tensin SH2 domains identified from combinatorial libraries.
Cyclic peptides provide attractive lead compounds for drug discovery and excellent molecular probes in biomedical research. In this work, a novel method has been developed for the high-throughput synthesis, screening, and identification of cyclic peptidyl ligands against macromolecular targets. Support-bound cyclic phosphotyrosyl peptide libraries containing randomized amino acid sequences and different ring sizes (theoretical diversity of 3.2 x 10(6)) were synthesized and screened against the SH2 domains of Grb2 and tensin. Potent, selective inhibitors were identified from the libraries and were generally more effective than the corresponding linear peptides. One of the inhibitors selected against the Grb2 SH2 domain inhibited human breast cancer cell growth and disrupted actin filaments. This method should be applicable to the development of cyclic peptidyl inhibitors against other protein domains, enzymes, and receptors.
Zhang
Yanyan
Y
Department of Chemistry and Ohio State Biochemistry Program, The Ohio State University, 100 West 18th Avenue, Columbus, Ohio 43210, USA.
Zhou
Shanggen
S
Wavreille
Anne-Sophie
AS
DeWille
James
J
Pei
Dehua
D
D020650:Combinatorial Chemistry Techniques; D018360:Crystallography, X-Ray; D051380:GRB2 Adaptor Protein / Q000037:antagonists & inhibitors* / Q000737:chemistry; D008840:Microfilament Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D010456:Peptides, Cyclic / Q000737:chemistry* / Q000494:pharmacology; D000070876:Tensins; D018909:src Homology Domains
D051380:GRB2 Adaptor Protein; C495948:GRB2 protein, human; D008840:Microfilament Proteins; D010456:Peptides, Cyclic; D000070876:Tensins