Hitting the hot spots: Scientist fine-tune GPCR targeting

In a recent issue of Science, researchers believe they have found a way to selectively target G protein-coupled receptors (GPCRs) with small-molecule compounds that interrupt protein-protein interactions.

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ROCHESTER, N.Y.—In a recent issue of Science, researchers at the University of Rochester Medical Center (URMC) and Farmington, Conn.-based University of Connecticut Health Center believe they have found a way to selectively target G protein-coupled receptors (GPCRs) with small-molecule compounds that interrupt protein-protein interactions. If widely applicable, the new method could dramatically expand the number of therapeutic strategies available in a market that already accounts for $200 billion in annual drug sales.
"GPCRs regulate many aspects of cellular physiology and unique subtypes are specifically distributed in individual tissues," says Dr. Alan Smrcka, URMC professor and lead researcher on the project. The involvement of GPCRs in various diseases makes them particularly attractive therapeutic targets. Current drugs targeting GPCRs include Coreg for congestive heart failure, Cozaar for high blood pressure, Zoladex for breast cancer, Buspar for anxiety and Clozaril for schizophrenia.
Many of these drugs work by interfering with the ability of the GPCR to translate signals from outside of the cell to other proteins within the cell, but this is where the challenge lies in developing drugs.
"Targeting protein complexes with small molecules is notoriously difficult because of the large flat protein surfaces involved that can provide lots of binding energy for large proteins but not necessarily small molecules," Smrcka explains. At the same time, companies would prefer to develop small-molecule drugs as they are more readily bioavailable and are more resistant to metabolism than larger peptides.
Using FlexX virtual screening software, the researchers screened almost 2,000 compounds from the National Cancer Institute for interactions with the protein-protein interaction site of a particular GPCR. They then tested the 85 compounds with the best score for their ability to inhibit binding of specific peptides.
Not only could the researchers block peptide binding, but they also found that they could perturb specific hotspots within the interface region that selectively targeted different biological functions of the GPCR, including inflammation and response to analgesia.
"Much of cellular physiology is governed by protein-protein interactions," Smrcka says. "What we and others have shown suggests a novel strategy for drug design because it indicates that these types of protein interfaces, involving 'hot spots' are amenable to pharmaceutical targeting.
"Imagine if we could identify 50 small molecules, with each one bringing about a specific set of changes in the behavior the hotspot. Taken together, this arsenal would grant us precise control over one of the most important biochemical switches in the body."
While this work has only been applied to GPCRs, its basic principles should be widely applicable to other disease states involving protein-protein interactions, a market that should approach $50 billion by 2010 according to a January 2005 report by Dr. Anil Sehgal for Drug & Market Development.
In a 2004 discussion about small-molecule protein-protein interaction inhbitors (SMPPIIs), Dr. Len Pagliaro and colleagues at Copenhagen-based BioImage said: "Application of SMPPII technology to new therapeutic fields will no doubt occur as our knowledge of the role of protein–protein interactions in other human disease increases. When combined with suitable high-throughput screening formats, such as protein translocation assays, it will be only a matter of time before drugs that act as SMPPIIs reach the clinic."
It is beginning to look as though they were right.

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