Development of molecular probes for second-site screening and design of protein tyrosine phosphatase inhibitors.
We report on the design, synthesis, and evaluation of a series of furanyl-salicyl-nitroxide derivatives as effective chemical probes for second-site screening against phosphotyrosine phosphatases (PTPs) using NMR-based techniques. The compounds have been tested against a panel of PTPs to assess their ability to inhibit a broad spectrum of these phosphatases. The utility of the derived compounds is illustrated with the phosphatase YopH, a bacterial toxin from Yersinia pestis. Novel chemical fragments were identified during an NMR-based screen for compounds that are capable of binding on the surface of YopH in regions adjacent the catalytic site in the presence of the spin-labeled compounds. Our data demonstrate the value of the derived chemical probes for NMR-based second-site screening in PTPs.
Vazquez
Jesus
J
Inflammation and Infectious Disease Center, Burnham Institute for Medical Research, 10901 North Torrey Pines Road, La Jolla, California 92037, USA.
Tautz
Lutz
L
Ryan
Jennifer J
JJ
Vuori
Kristiina
K
Mustelin
Tomas
T
Pellecchia
Maurizio
M
D001425:Bacterial Outer Membrane Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D020134:Catalytic Domain; D003497:Cyclic N-Oxides / Q000138:chemical synthesis* / Q000737:chemistry; D005663:Furans / Q000138:chemical synthesis* / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D012459:Salicylates / Q000138:chemical synthesis* / Q000737:chemistry; D013113:Spin Labels / Q000138:chemical synthesis*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D001425:Bacterial Outer Membrane Proteins; D003497:Cyclic N-Oxides; D005663:Furans; D012459:Salicylates; D013113:Spin Labels; D017027:Protein Tyrosine Phosphatases; C067571:yopH protein, Yersinia