Exploiting ligand conformation in selective inhibition of non-ribosomal peptide synthetase amino acid adenylation with designed macrocyclic small molecules

J Am Chem Soc. 2007 Jun 27;129(25):7752-3. doi: 10.1021/ja0721521. Epub 2007 Jun 2.

Abstract

Macrocyclic aminoacyl-AMP analogs have been developed to inhibit non-ribosomal peptide synthetase amino acid adenylation domains selectively by mimicking a cisoid ligand binding conformation observed in crystal structures. In contrast, these macrocycles do not inhibit aminoacyl-tRNA synthetases, which are mechanistically closely related but bind their ligands in a distinct transoid conformation. The macrocycles contain a two- or three-carbon linker between Cβ of the amino acid moiety and C8 of the adenine ring and a sulfamate in place of the phosphate group. These compounds are potent inhibitors of the cysteine adenylation domain activity of the yersiniabactin siderophore synthetase HMWP2 and, unlike the corresponding linear aminoacyl-AMP analogs, do not inhibit protein translation in vitro. Selective small molecule inhibitors of non-ribosomal peptide synthesis should provide a powerful means to study the biological functions of non-ribosomal peptide natural products and a potential avenue to develop novel antibiotics.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acids / chemistry*
  • Amino Acids / metabolism*
  • Ligands
  • Macrocyclic Compounds / chemistry*
  • Macrocyclic Compounds / metabolism*
  • Molecular Structure
  • Peptide Synthases / antagonists & inhibitors*
  • Peptide Synthases / chemistry
  • Peptide Synthases / metabolism
  • Protein Structure, Tertiary

Substances

  • Amino Acids
  • Ligands
  • Macrocyclic Compounds
  • Peptide Synthases