<b> </b>Most of neurodegenerative diseases share a common feature, which is the abnormal accumulation of proteins in the brains of patients into harmful structures known as amyloid aggregates. Much anti-amyloid effort has focused on screening compounds that delay, prevent or disrupt the amyloid formation. However, progress has been hampered by a lack of precise knowledge of the amyloid structure. An integrated approach, combining computational methods and amyloid structures, aims to ease this major bottleneck of structure-based drug discovery in neurodegenerative diseases. Knowledge of the atomic structure of steric zipper segment of amyloid fibers, when coupled with computational methods, enables the discovery of amyloid inhibitors.<br/><br/>Amyloid plaques and neurofibrillary tangles, composed of amyloid aggregates of beta-amyloid (Aβ) and tau protein, have been linked to Alzheimer’s disease and other tauopathies. Increasing evidence indicates those aggregates consist of highly toxic soluble oligomers, each containing a few misfolded monomers, and large insoluble amyloid fibrils, which might be less toxic. The recently determined atomic structure of a ligand-binding segment of the amyloid-beta (Aβ) protein permits us to screen inhibitors of amyloid toxicity which binds to amyloid fibers, reducing the concentration of toxic oligomers. After we applied computational docking algorithms to search vast compound databases, nearly a dozen lead compounds with diverse chemical structures were identified to reduce the cytotoxicity of Aβ fibers on mammalian cells, without reducing the number of fibers (Jiang, et al., eLife 2013). Structure-activity relationship studies of the fiber-binding compounds and their derivatives lead to further improvement. A pharmaceutically active compound, derived from our lead compounds, modulate the process of Aβ aggregation and inhibits the Aβ cytotoxicity in our cell-based assay, at the level comparable with Epigallocatechin gallate, an effective compound from screening. Our results support that compound binding increases fiber stability and decreases fiber toxicity, perhaps by shifting the equilibrium of Aβ from oligomers to fibers. The success of our structure-based amyloid inhibitor discovery demonstrated the atomic structures of steric zipper segments reassemble the structural features of amyloid fibers, offering a new potential treatment for anti-amyloid therapeutics.

Modulate protein aggregation and amyloid toxicity by structure-based computational approaches

251st National Meeting (2016)

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