Affinity-Based Inhibition of β-Amyloid Toxicity

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Abstract
Strategies for interfering with protein aggregation are important for elucidating and controlling the pathologies of amyloid diseases. We have previously identified compounds that block the cellular toxicity of the β-amyloid peptide, but the relationship between their ability to inhibit toxicity and their affinity for Aβ is unknown. To elucidate this relationship, we have developed an assay capable of measuring the affinities of small molecules for β-amyloid peptide. Our approach employs immobilized β-amyloid peptide at low density to minimize the problems that arise from variability in the β-amyloid aggregation state. We found that low-molecular weight (MW of 700−1700) ligands for β-amyloid can be identified readily by using surface plasmon resonance. The best of these bound effectively (Kd ∼ 40 μM) to β-amyloid. The affinities measured for peptides in the SPR assay correspond to results from Aβ cell toxicity assays. The most potent ligands for immobilized β-amyloid are the most potent inhibitors of the neuronal cell toxicity of β-amyloid. Compounds with dissocation constants above ∼100 μΜ did not show significant activity in the cell toxicity assays. Our data support the hypothesis that ligands exhibiting greater affinity for the β-amyloid peptide are effective at altering its aggregation and inhibiting cell toxicity.