Mass Spec Detects and Images Protein-Drug Complex in Tissue

Researchers in the UK report a new technique that can analyze how drug molecules bind to proteins in tissue samples—an advance that may provide a more efficient route to drug discovery and development.

Early-stage drug discovery often takes place in cell cultures, which enable the effects of different compounds to be tested on specific biological targets involved in various diseases. While valuable for testing the efficacy of potential drugs, cell cultures do not capture the full effects of the physiological environment.

The new method, developed by researchers at the University of Birmingham in collaboration with biopharmaceutical company AstraZeneca, uses mass spectrometry, an analytical tool commonly used for identifying the properties of molecules within a sample. It enables researchers to use real tissue samples to assess which proteins the drug will bind to in the body and therefore how effective it is likely to be against the target. Being able to pinpoint the interaction between the drug and the protein can provide valuable insight to guide drug discovery.

 “Usually in early-stage drug discovery, measurements are taken outside of the physiological environment, so when researchers move onto testing drugs in tissue, they can fail because they have interactions that were not expected,” says lead researcher Professor Helen Cooper. “Identifying the drug protein interaction at this early stage, however, is incredibly hard. Using mass spectrometry on proteins is often compared to making an elephant fly. What we’ve done is add an unsecured hat—the drug molecule—to the elephant, and measured the whole process. It’s exciting because it opens up the possibility of being able to follow the route of a drug through the body. By identifying which proteins it interacts with scientists will be able to predict at an earlier stage whether or not it will have the desired therapeutic effect.”

To confirm the efficacy of the method, the researchers used tissue taken from the livers of rats dosed with bezafibrate, a drug commonly used to treat high cholesterol. They used mass spectrometry on thin sections of tissue to detect the drug molecule and the specific fatty acid binding protein to which it attaches to form a complex. The researchers were also able to measure both the varying amounts of this complex in the liver over time, and how it spreads through the tissue.

 “This research builds on a long-standing collaboration between AstraZeneca and the University of Birmingham and exemplifies what can be done when we combine complementary skills to address significant unmet need,” says AstraZeneca lead Professor Richard Goodwin, Senior Director, Imaging Sciences. “This research will continue to support drug discovery and help accelerate us bringing new medicines to patients.”

Next steps for the team include improving the sensitivity of the technique and extending it to other types of drug compounds. They hope it can be developed for use in human tissue, taken from biopsies, to provide a greater understanding of why drugs work differently in different patients.

The study was published in a recent issue of Angewandte Chemie.