title: Structure-based design of a macrocyclic inhibitor for peptide deformylase.
abstract: A macrocyclic, peptidomimetic inhibitor of peptide deformylase was designed by covalently cross-linking the P1' and P3' side chains. The macrocycle, which contains an N-formylhydroxylamine side chain as the metal-chelating group, was synthesized from a diene precursor via olefin metathesis using Grubbs's catalyst. The cyclic inhibitor showed potent inhibitory activity toward Escherichia coli deformylase (K(I) = 0.67 nM) and antibacterial activity against both Gram-positive and Gram-negative bacteria (MIC = 0.7-12 microg/mL).
authors.affiliation: Department of Chemistry and Ohio State Biochemistry Program, The Ohio State University, 100 West 18th Avenue, Columbus, Ohio 43210, USA.
authors.forename: Xubo
authors.initials: X
authors.lastname: Hu
authors.forename: Kiet T
authors.initials: KT
authors.lastname: Nguyen
authors.forename: Christophe L M J
authors.initials: CL
authors.lastname: Verlinde
authors.forename: Wim G J
authors.initials: WG
authors.lastname: Hol
authors.forename: Dehua
authors.initials: D
authors.lastname: Pei
mesh_terms: D000581:Amidohydrolases; D000626:Aminopeptidases / Q000037:antagonists & inhibitors*; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002614:Chelating Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006094:Gram-Positive Bacteria / Q000187:drug effects; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D018716:Molecular Mimicry; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D002614:Chelating Agents; D004791:Enzyme Inhibitors; D010456:Peptides, Cyclic; D000626:Aminopeptidases; D008666:Metalloendopeptidases; D000581:Amidohydrolases; C084507:peptide deformylase