A chemoenzymatic approach to glycopeptide antibiotics

被引：144

作者：

Lin, HN ^{[1
]}

Walsh, CT ^{[1
]}

机构：

[1] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA

来源：

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY | 2004年 / 126卷 / 43期

关键词：

D O I：

10.1021/ja045147v

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

Many biologically active natural products are constrained by macrocyclization and modified with carbohydrates. These two types of modifications are essential for their biological activities. Here we report a chemoenzymatic approach to make carbohydrate-modified cyclic peptide antibiotics. Using a thioesterase domain from the decapeptide tyrocidine synthetase, 13 head-to-tail cyclized tyrocidine derivatives were obtained with one to three propargylglycines incorporated at positions 3-8. These cyclic peptides were then conjugated to 21 azido sugars via copper(I)-catalyzed cycloaddition. Antibacterial and hemolytic assays showed that the two best glycopeptides, Tyc4PG-14 and Tyc4PG-15, have a 6-fold better therapeutic index than the natural tyrocidine. We believe this method will also be useful for modifying other natural products to search for new therapeutics.

引用

页码：13998 / 14003

页数：6

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