Fluorescent Mu Selective Opioid Ligands from a Mixture Based Cyclic Peptide Library

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• 作者：Yangmei Li ; Colette T. Dooley ; Jaime A. Misler ; Ginamarie Debevec ; Marc A. Giulianotti ; Margaret E. Cazares ; Laura Maida ; Richard A. Houghten
• 刊名：ACS Combinatorial Science
• 出版年：2012
• 出版时间：December 10, 2012
• 年：2012
• 卷：14
• 期：12
• 页码：673-679
• 全文大小：407K
• 年卷期：v.14,no.12(December 10, 2012)
• ISSN：2156-8944

文摘

A positional scanning cyclic peptide library was generated using a penta-peptide thioester scaffold. Glycine was fixed at position R¹. Diaminopropionic acid was fixed at position R³, with its 纬-amino attaching to an anthraniloyl group. Positions R² and R⁴ contained 36 l- and d- amino acids and position R⁵ contained 19 l- amino acids. Cyclization was performed in a mixture of acetonitrile and 1.5 M aqueous imidazole solution (7:1 v/v) at room temperature for 5 days. No significant cross-oligomerization was detected under the cyclization conditions. The library was screened in a binding assay for mu opioid receptor, identifying the active amino acid mixture at each position. A total of 40 individual cyclic peptides were identified and synthesized by the combinations of the most active amino acid mixtures found at three positions 5 脳 4 脳 2. Two cyclic peptides exhibited high binding affinities to opioid receptor. The most active cyclic peptide in the library was yielded to have Tyr at R², d-Lys at R⁴, and Tyr at R⁵. Further investigation on this compound revealed the side chain-to-tail isomer to have greater binding affinity (14 nM) than the head-to-tail isomer (39 nM). Both isomers were selective for the mu-opioid receptor.

Keywords:

lic+peptide&qsSearchArea=searchText">cyclic peptide; library&qsSearchArea=searchText">positional scanning library; lic+peptide+library&qsSearchArea=searchText">synthetic cyclic peptide library; ligand&qsSearchArea=searchText">opioid ligand; ligand&qsSearchArea=searchText">mu selective ligand; fluorescent label