期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 110, 期 40, 页码 E3753-E3760出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1311706110
关键词
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资金
- National Cancer Institute [P01 CA95471]
- Donald J. and Jane M. Cram Endowment
- National Science Foundation [DGE-0707424, CHE-1048804]
- Direct For Mathematical & Physical Scien [1048804] Funding Source: National Science Foundation
- Division Of Chemistry [1048804] Funding Source: National Science Foundation
Peptide-protein interactions are important mediators of cellular-signaling events. Consensus binding motifs (also known as short linear motifs) within these contacts underpin molecular recognition, yet have poor pharmacological properties as discrete species. Here, we present methods to transform intact peptides into stable, templated macrocycles. Two simple steps install the template. The key reaction is a palladium-catalyzed macrocyclization. The catalysis has broad scope and efficiently forms large rings by engaging native peptide functionality including phenols, imidazoles, amines, and carboxylic acids without the necessity of protecting groups. The tunable reactivity of the template gives the process special utility. Defined changes in reaction conditions markedly alter chemoselectivity. In all cases examined, cyclization occurs rapidly and in high yield at room temperature, regardless of peptide composition or chain length. We show that conformational restraints imparted by the template stabilize secondary structure and enhance proteolytic stability in vitro. Palladium-catalyzed internal cinnamylation is a strong complement to existing methods for peptide modification.
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