期刊
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
卷 58, 期 44, 页码 15904-15909出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.201908713
关键词
cyclic peptides; HDAC8; N-epsilon-acryloyl-lysine; phage display; proximity-driven cyclization
资金
- National Institute of Health [R01CA161158]
- Cancer Prevention and Research Institute of Texas [RP170797]
- Welch Foundation [A-1715]
Superior to linear peptides in biological activities, cyclic peptides are considered to have great potential as therapeutic agents. To identify cyclic-peptide ligands for therapeutic targets, phage-displayed peptide libraries in which cyclization is achieved by the covalent conjugation of cysteines have been widely used. To resolve drawbacks related to cysteine conjugation, we have invented a phage-display technique in which its displayed peptides are cyclized through a proximity-driven Michael addition reaction between a cysteine and an amber-codon-encoded N-epsilon-acryloyl-lysine (AcrK). Using a randomized 6-mer library in which peptides were cyclized at two ends through a cysteine-AcrK linker, we demonstrated the successful selection of potent ligands for TEV protease and HDAC8. All selected cyclic peptide ligands showed 4- to 6-fold stronger affinity to their protein targets than their linear counterparts. We believe this approach will find broad applications in drug discovery.
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