title: NMR-based design and evaluation of novel bidentate inhibitors of the protein tyrosine phosphatase YopH.
abstract: We describe the use of a furanyl salicyl nitroxide derivative ('spin-labeled' compound), as a paramagnetic phosphotyrosine mimetic, to carry out a second-site screening by NMR against the PTPase YopH from Yersinia pestis. Using such a fragment-based screening approach we identified several small molecules targeting YopH that bind at sites adjacent to the spin-labeled compound. These second-site fragments were subsequently used to design and synthesize bidentate YopH inhibitors with submicromolar in vitro inhibition, selectivity against the human PTPase PTP1B, and cellular activity against Y. pseudotuberculosis. These initial compounds could result useful in elucidating the structural determinants necessary for YopH inhibition and may help in the design of even more active, selective and cell permeable compounds for the development of novel therapies against Yersiniae.
authors.affiliation: Infectious and Inflammatory Disease Center and Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037 , USA.
authors.forename: Marilisa
authors.initials: M
authors.lastname: Leone
authors.forename: Elisa
authors.initials: E
authors.lastname: Barile
authors.forename: Jesus
authors.initials: J
authors.lastname: Vazquez
authors.forename: Angel
authors.initials: A
authors.lastname: Mei
authors.forename: Donald
authors.initials: D
authors.lastname: Guiney
authors.forename: Russel
authors.initials: R
authors.lastname: Dahl
authors.forename: Maurizio
authors.initials: M
authors.lastname: Pellecchia
mesh_terms: D001425:Bacterial Outer Membrane Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D015195:Drug Design; D006367:HeLa Cells; D006801:Humans; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular / Q000379:methods*; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000494:pharmacology*; D015007:Yersinia / Q000187:drug effects; D015009:Yersinia Infections / Q000188:drug therapy*
chemical_list: D001425:Bacterial Outer Membrane Proteins; D054852:Small Molecule Libraries; D017027:Protein Tyrosine Phosphatases; C067571:yopH protein, Yersinia
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