A General Method for Discovering Inhibitors of Protein−DNA Interactions Using Photonic Crystal Biosensors

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Abstract
Protein−DNA interactions are essential for fundamental cellular processes such as transcription, DNA damage repair, and apoptosis. As such, small molecule disruptors of these interactions could be powerful tools for investigation of these biological processes, and such compounds would have great potential as therapeutics. Unfortunately, there are few methods available for the rapid identification of compounds that disrupt protein−DNA interactions. Here we show that photonic crystal (PC) technology can be utilized to detect protein−DNA interactions, and can be used in a high-throughput screening mode to identify compounds that prevent protein−DNA binding. The PC technology is used to detect binding between protein−DNA interactions that are DNA-sequence-dependent (the bacterial toxin−antitoxin system MazEF) and those that are DNA-sequence-independent (the human apoptosis inducing factor (AIF)). The PC technology was further utilized in a screen for inhibitors of the AIF−DNA interaction, and through this screen aurin tricarboxylic acid was identified as the first in vitro inhibitor of AIF. The generality and simplicity of the photonic crystal method should enable this technology to find broad utility for identification of compounds that inhibit protein−DNA binding.