title: A chemoenzymatic approach to glycopeptide antibiotics.
abstract: 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.
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Armenise 616, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Hening
authors.initials: H
authors.lastname: Lin
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Walsh
mesh_terms: D000480:Alkynes / Q000737:chemistry; D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000096:biosynthesis* / Q000138:chemical synthesis* / Q000494:pharmacology; D001386:Azides / Q000737:chemistry; D002241:Carbohydrates / Q000737:chemistry; D003500:Cyclization; D005998:Glycine / Q000031:analogs & derivatives* / Q000737:chemistry; D006020:Glycopeptides / Q000096:biosynthesis* / Q000138:chemical synthesis* / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D009005:Monosaccharides / Q000737:chemistry
chemical_list: D000480:Alkynes; D000900:Anti-Bacterial Agents; D001386:Azides; D002241:Carbohydrates; D006020:Glycopeptides; D009005:Monosaccharides; C009055:propargylglycine; D005998:Glycine