| Affiliation: | 1. Infectious and Inflammatory Disease Center and Cancer Center, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Rd, 92037 La Jolla, CA, USA Institute of Biostructures and Bioimaging-CNR, Via Mezzocannone 16, 80134 Naples, Italy;2. Infectious and Inflammatory Disease Center and Cancer Center, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Rd, 92037 La Jolla, CA, USA;3. Department of Medicine, University of California at San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA |
| 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. |
