Inhibition of β-amyloid fibrillization by directed evolution of a β-sheet presenting miniature protein

We describe the directed evolution of a miniature β-sheet protein for targeting β-amyloid oligomers implicated in Alzheimer's disease. Circular dichroism spectroscopy, thermal denaturation experiments, and immunoglobulin binding assays established that our β-amyloid-targeted miniature protein, TJ10, presents a well-folded thermostable β-sheet. TJ10 was found to prevent β-amyloid fibrillization at stoichiometric concentrations and was also an effective inhibitor at substoichiometric concentrations. Thus our results provide a new and potent β-sheet chemical template for effectively targeting β-amyloid while also demonstrating a general strategy for targeting proteins implicated in other amyloidogenic diseases.