I6 Natural product-based protein amyloid inhibitors

Abstract

Toxic protein amyloid formation has been implicated in more than a dozen protein misfolding diseases such as Alzheimer’s disease, Parkinson’s disease, and type 2 diabetes. Currently there are no effective disease-modifying drugs available. One common therapeutic strategy is to discover and develop protein amyloid inhibitors that can slow down, prevent, or remodel toxic amyloids. Natural products are a major class of amyloid inhibitors, and several dozens of natural product-based amyloid inhibitors have been identified and characterized in recent years. Using amyloidogenic proteins amylin, amyloid beta-peptide, and tau as model systems, we screened libraries of natural compounds used in Complementary and Alternative Medicine. We identified multiple potent inhibitors, including rosmarinic acid and baicalein (200 nM and 1 μM respectively in apparent IC 50 ) [1] . These compounds disaggregate amyloidogenic protein fibrils, significantly reduce protein amyloid-induced cytotoxicity and toxic amyloid oligomers in circulating sera and/or cerebrospinal fluid from diseased animal models. Dissecting the functional groups of these compounds, we demonstrated, for the first time to our knowledge, that the vicinal hydroxyl groups of the catechol groups played key functional roles in amyloid inhibition in more than two dozen catechol-containing compounds, including many plant- and fruit-derived flavonoids and other phenolic compounds [2] . Compounds with multiple catechol groups, such as rosmarinic acid, exhibited additive effects. We provided further mass spectrometric evidence that incubating several of these catechol-containing inhibitors with amyloidogenic proteins leads to covalent adducts consistent with Schiff base conjugation mechanism to interfere with toxic amyloid formation. Consistent with forming covalent adducts via the mechanism of quinone intermediates, we demonstrated that many catechol-containing natural products significantly increase amyloid inhibition effects under autooxidation or oxidizing conditions. Lastly, I will discuss our approach to enhance certain natural product solubility/bioavailability by engineering natural compound-incorporating nanoparticles [3] . Acknowledgement This work is in part supported by Virginia Tech new faculty start-up funds, Commonwealth Health Research Board (CHRB), Alzheimer’s and Related Diseases Research Award Fund (ARDRAF) from Virginia Center on Aging, Diabetes Action Research and Education Foundation (DAREF), and Virginia Tech Center for Drug Discovery (VTCDD).