Research: Investigations

Drug-Protein Complexes as Inhibitors of Protein-Protein Interactions: Using the Body's Own Proteins to Fight Disease

The commonly observed "rules" of drug discovery suggest that a successful drug candidate should be small. This strategy arose from years of observations on what constitutes a "good" drug and has been validated countless times. The problem with this strategy is that small molecules are not effective against certain classes of potential drug targets. For example, protein-protein interactions are typically resistant to inhibition by small molecules. Protein-protein interactions involve the binding of one protein to another and these contacts are important for many diseases, such as Alzheimer's disease. One of the main reasons that protein-protein interactions are difficult targets is that proteins are very large compared to the drug. Thus, rather than blocking a protein-protein interaction, small drug-like compounds tend to be swallowed up. A useful analogy is to consider a dime placed between two bricks. The dime doesn't prevent the bricks from assembling. So, how does one get around this problem but still have the drug follow the well established "rules"?

The Gestwicki laboratory is developing a method for making small molecules appear much bigger than they actually are. The trick we are using involves giving the small molecule the ability to form a complex with a protein called FKBP. FKBP is present at high levels in people and has roughly the same size as many proteins involved in protein-protein interactions. The molecules being synthesized in the lab are able to bind to FKBP on one end and to a protein involved in protein-protein interactions on the other. Thus, the drug-FKBP complex, with its large size, becomes better at blocking the protein-protein interaction. Importantly, the small drug doesn't get bigger until after it reaches its target, thus fulfilling the requirements of the "rules."

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The protein-protein interactions being targeted in the Gestwicki laboratory are involved in neurodegenerative problems, such as Alzheimer's and Huntington's diseases. Using bifunctional molecules (i.e. molecules that bind to a protein on each end), they hope to develop better tools for characterizing these symptoms and build new strategies to combat these diseases. The goal is to enlist the patient's own proteins (such as FKBP) in the fight against disease.

— Jason Gestwicki, PhD, December 2005