Cyclic Peptidyl Inhibitors of Grb2 and Tensin SH2 Domains Identified from Combinatorial Libraries

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• 作者：Yanyan Zhang ; Shanggen Zhou ; Anne-Sophie Wavreille ; James DeWille ; Dehua Pei
• 刊名：Journal of Combinatorial Chemistry
• 出版年：2008
• 出版时间：March 2008
• 年：2008
• 卷：10
• 期：2
• 页码：247 - 255
• 全文大小：733K
• 年卷期：v.10,no.2(March 2008)
• ISSN：1520-4774

文摘

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 × 10⁶) 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.