The Utility of NMR in the Design of BAmyloid Inhibitors

Michael Zagorski, PhD
Case Western Reserve University (Cleveland, OH)
Year Awarded:
2000
Grant Duration:
April 1, 2000 to March 31, 2002
Disease:
Alzheimer's Disease
Award Amount:
$198,050
Grant Reference ID:
A2000056
Award Type:
Standard
Award Region:
US Midwestern

The Utility of NMR in the Design of BAmyloid Inhibitors

Details


The production of amyloid plaque from single molecules of Ab42 appears to go through predictable steps, beginning with the accumulation of larger, soluble Ab complexes that undergo changes that result in the formation of insoluble plaques. These steps are accompanied by structural changes in the individual Ab42 molecules into a form called a beta-sheet. Dr. Zagorski is applying Nuclear Magnetic Resonance imaging to study structural changes in Ab42 as well as other molecules known to inhibit amyloidosis. This information will then be used to construct three-dimensional models of Ab42 and inhibitors. These models should in turn allow for the design of better inhibitors of Ab accumulation that could help develop better treatments or even a prevention of AD.

Publications

Hou, L., Shao, H., Zhang, Y., Li, H., Menon, N.K., Neuhaus, E.B., Brewer, J.M., Vitek, M.P., Makula, R.A., Przybyla, A.B., and Zagorski, M.G. (2004) Solution NMR studies of the A beta(1-40) and A beta(1-42) peptides establish that the Met35 oxidation state affects the mechanism of amyloid formation. J. Am Chem Soc. 126(7):1992-2005  

Poeggeler, B., Miravalle, L., Zagorski, M.G., Wisniewski, T., Chyan, Y.J., Zhang, Y., Shao, H., Bryant-Thomas, T., Frangione, B., Ghiso, J., and Pappolla, M. (2001) Melatonin reverses the profibrillogenic activity of apolipoprotein E4 on the Alzheimer amyloid Abeta peptide. Biochemistry. 40(49):14995-5001. [Alzforum Recommended Paper]  

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