Work

Exploiting Ligand Conformation in Selective Inhibition of Non-Ribosomal Peptide Synthetase Amino Acid Adenylation with Designed Macrocyclic Small Molecules

Year: 2007

Type: article

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.

Source: Journal of the American Chemical Society

DOI: 10.1021/ja0721521

Authors: Justin S. Cisar, Julian A. Ferreras, Rajesh K. Soni, Luis E. N. Quadri, Derek S. Tan

Institutions: Memorial Sloan Kettering Cancer Center, Cornell University, Weill Cornell Medicine

Language: English

Topic: Microbial Natural Products and Biosynthesis

Subfield: Pharmacology

Field: Medicine

Domain: Health Sciences

Open Access status: green

Funder: National Institute of Allergy and Infectious Diseases

Awards: MACROPHAGES, DENDRITIC CELLS AND PATHOGENS, Virulence-conferring siderophore biosynthesis inhibitors