Almost a year after winning his Nobel Prize for studies of G-protein coupled receptors, Dr. Robert Lefkowitz and pharmaceutical companies are placing a new focus on the receptors' potentiality to become drug targets.
Lefkowitz, James B. Duke professor of medicine and professor of biochemistry and immunology, has joined pharmaceutical company Lexicon Pharmaceuticals and Nuevolution—a molecular research lab—in examining GPCRs through an extensive compound screening process. The parties will screen different compounds in an effort to find ones that will bind with GPCRs. The focus on GPCRs as drug targets can unlock the potential for target specific, disease specific and side effect-free drugs.
“This is a big deal because this opens the door to a whole new type of drug,” said Lefkowitz, who is the first standing faculty member to win a Nobel Prize.
GPCRs are molecules located in the cell membrane with which drugs and hormones interact. There are 1,000 different kinds of GPCRs, which vary in function, including the regulation of smell, taste and vision. About half of the pharmaceutical drugs sold today target these receptors.
Nuevolution Chief Scientific Officer Thomas Franch said that Lexicon formed a deal with Nuevolution five years ago to use part of their Chemetics technology—a library of molecules to be used in the drug screening process. Lefkowitz, a scientific advisor on Lexicon’s board, then approached Lexicon with the idea for a GPCR-focused collaboration.
"Typically a large library of compounds that might be screened in the pharmaceutical industry to come up with a new drug against a particular target might be anywhere from one to several million compounds," Lefkowitz said. "But the libraries that these companies have created have a billion different molecules."
The Chemetics technology tags each molecule with a piece of DNA, and if a molecule and receptor interact they can sequence the DNA to identify the molecule.
“It’s like we’re using the receptor as a bait, and it’s a long process, but you’re just fishing [to find] what kind of compounds bind to the receptors,” said Duke assistant professor in medicine Seungkirl Ahn, who is a member of Lefkowitz's lab.
G-proteins, as well as β-arrestins, transmit signals that either cause unwanted side effects or the desired result. With the Chemetics technology, the researchers can find which compounds will block the unwanted signals, thereby eliminating unwanted side effects.
Lefkowitz explained the therapeutic benefits that can stem from this type of research.
Before the age of steroids, athletes abused the performance-enhancing drug Clenbuterol to gain muscle mass, Lefkowtiz said. This drug, however, must be used intermittently because of side effects that include sweating, fast heart rate, nervousness and diarrhea.
The side effects, Lefkowitz noted, all go through the G-proteins. The basis for the muscle-building effect was never truly known to scientists, but Lefkowitz entertains the idea that it may go through the β-arrestins. If researchers used the technology to find a compound that binds to the G-protein instead of the β-arrestin, athletes could build muscle without the undesirable side effects.
"So you might say, 'you're interested in being the czar of the new era of doping,'" he said. "And the answer is 'no that's not what I'm after.'"
Lefkowitz went on to describe how the research would revolutionize the drug industry, as one of the biggest medical unmet needs is frailty in the elderly and the chronically ill.
Each party will play a specific role in the collaboration. Nuevolution and Lexicon supply the molecule libraries. In addition, the Howard Hughes Medical Institute has contributed grant money to Lefkowitz’s lab. Lefkowitz’s lab will use both libraries for the screening process. At this time, no students will be involved in this specific research project.
The past two years since the initial decision to form the research group have been tangled in legal agreements, Ahn said.
The decision of which party will have the rights to a potential discovery is still under confidentiality, Franch said.
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