An H/F/X/Y Fast-MAS NMR Probe Particularly for Alzheimer’s and Cancer Research

DESCRIPTION provided by applicant More than of current drugs and a much greater fraction of those in development are fluorinated including such block busters as Prozac Lipitor and Ciprobay Steady progress over the past decade has shown magic angle spinning MAS solid state NMR ssNMR to be arguably the most powerful analytical tool for studying macro molecular structures and their dynamics Yet MAS probes suitable for the needed multi channel studies of fluorinated drugs and their interactions are not available for high field NMR instruments While a few H F X channel MAS probes with inadequate spinning speeds and spectral resolution have been demonstrated for fields up to MHz the technical challenges have been seen as too daunting at higher fields because of the difficulties of known single coil rf circuits in handling close resonances at high frequencies Quad tuned H F X Y MAS probes have apparently never been made even for low fields For solution NMR on the other hand four channel multinuclear H F X H probes have recently become more readily available and such have proven to be extremely valuable for identification and characterization using H N F C and F H N methods of active fragments their binding to soluble proteins and their effects on such protein protein interactions The problem is that such methods donandapos t work with insoluble proteins such as the aggregates and fibrils that are central to Alzheimerandapos s disease AD Parkinsonandapos s disease PD and probably even prion mediated diseases The amyloid beta A cascade hypothesis is beginning to bring unity to the field of neurodegenerative diseases but a key tool for understanding aggregate progression and treatment beyond the stages of the initial seeds is not available This Phase I proposal seeks funding to develop build and test a prototype H F X Y fast MAS probe based on a novel andquot single coilandquot rf circuit optimized for F detection with simultaneous irradiation or detection on ny or all of the other channels and suitable for MAS at fields from T with rotor diameters from mm Analysis suggests that a substantial portion of the spectral line broadening seen in many MAS experiments is from J couplings which is not averaged by MAS to heteronuclei and spinner dependent effects thermal gradients axial vibration and magnetism The ability to simultaneously decouple H H and C or N during F detection with fast MAS in a spinner optimized for high resolution with a circuit compatible with B up to at least MHz will permit a dramatic increase in spectral resolution and sensitivity on for example F labeled ligands in amyloid assemblies and their precursor aggregates or in F labeled DNA carcinogen adducts The novel probe would allow the powerful suite of NMR acquisition and automated structure determination protocols developed for solution NMR which rely mostly on indirect detected triple and quad resonance schemes to be successfully applied to rigid fluorinated samples smaller than a milligram The Phase II probe will be compatible with automated sample exchange and sample temperatures from K to K Moreover it will be essentially devoid of problematic background signals for all the primary nuclides H F P C H N and O and it will be tunable to virtually all combinations of interest thereby making it also invaluable in such areas as metabolism materials science catalysis and sustainable energy PUBLIC HEALTH RELEVANCE Thousands of researchers are regularly using Nuclear Magnetic Resonance NMR techniques with a majority of the applications driven by the need for structure and function determination in biological macromolecules and pharmaceuticals The advances developed under this project will allow these laboratories to extend their methods to novel fluorinated drug developments showing promise for the treatment of Alzheimerandapos s disease and cancers