THE FULL MONTY ON DRUG TARGETS
Seven years ago, Bryan Roth's lab at the University of North Carolina at Chapel Hill (UNC) found that the drugs pergolide and cabergoline activate a cellular receptor called 5-HT2b, which is found on heart valves.
In January of this year, clinical trials revealed deadly heart problems associated with pergolide and cabergoline. These drugs, which are "ergot-derived dopamine receptor agonists" had been used to treat Parkinson's disease. They triggered heart-valve disease in nearly one-third of the patients in the trials.
"I was happy we were right," says Roth, "but unhappy that all these people were exposed to these drugs when we had predicted this a few years before. As side effects go, this is pretty astronomical." It turns out that overstimulation of 5-HT2b causes the valve to grow so large that it can't close tight - like a door too big for its jam. That lets blood leak through the valve, which reduces the efficiency of the heart.
Roth is a pioneer of receptoromics, the massively parallel screening of drug compounds against a wide spectrum of receptors. His lab focuses mainly on G-protein coupled receptors (GPCRs), which represent the molecular targets for 30% of all approved medications. GPCRs are a large protein family, accounting for more than one percent of the human proteins. Employing functional and binding assays and microarrays to observe drug actions on cloned receptors, receptoromics can reveal unexpected side effects, as it did with the Parkinson's drugs, but also novel drug uses. Roth's goal is to screen over 2,500 drug compounds against more than 300 GPCRs for side-effects. On a typical day the team can screen over 200 compounds.
To help identify compounds that are psychoactive, Roth runs the National Institute of Mental Health's Psychoactive Drug Screening Program. Through this program, other scientists can send in novel compounds, which are screened against a range of targets, including central nervous system channels, receptors, and transmitters - all cloned from human or rat. For academic researchers, compounds are screened for free.
Roth's facility has an advantage over similar academic labs because "other universities have a large drug set and screen it at one target at a time" while his procedures probe hundreds of targets simultaneously. Overall, Roth describes his lab as a kind of biotech or pharmaceutical company, but "instead of making money, we publish our information" in an online database (https://kidbdev.med.unc.edu/pdsp/), which is available for researchers in academia and industry.
Receptoromics is a boon to medicine, says Bruce Conklin, an investigator in the Gladstone Institute of Cardiovascular Disease. He has collaborated with Roth on related research and believes that the universe of patentable new drug molecules is limited. Roth recommends that industry scientists use both animal models and parallel screening against multiple targets. That's how the Roth Lab discovered that drugs for Parkinson's, some migraine medications, and drugs for appetite loss (such as Phen/Fen) stimulate the same receptor, 5-HT2b. He proposes that the pharmaceutical industry to screen every drug for the same effects as pergolide and cabergoline, before they go into clinical trials. "It's a very simple assay to do. There's nothing magical about the technology." He adds, "It would be trivial for any drug company to screen all approved drugs for this activity."
