With a four-year, $26,975,142 cooperative agreement from the Defense Advanced Research Project Agency (DARPA), Roth and colleagues will use new structural biology and computational approaches to create new medicines that work rapidly and effectively without serious side effects.
“Depression, anxiety, and substance abuse affect large segments of the population. Creating safe, rapidly acting and more effective medications would revolutionize the treatment of these disorders thereby diminishing death and disability,” said Roth, who also directs the National Institute of Mental Health Psychoactive Drug Screening Program, based at UNC-Chapel Hill. “Although drugs like ketamine and potentially psilocybin have rapid antidepressant actions, their hallucinogenic, addictive, and disorienting side effects make their clinical use limited. Our team has developed innovative methods and technologies to overcome these limitations with the goal of creating better medications to treat these neuropsychiatric conditions.”
The research project includes Georgios Skiniotis, PhD, and Ron Dror, PhD, from Stanford University; Jian Jin, PhD, from Icahn School of Medicine at Mt. Sinai; Brian Shoichet, PhD, and Nevan Krogan, PhD, from UC-San Francisco; and William Wetsel, PhD, from Duke University.
Approximately 30 percent of FDA approved medications target molecules on the surface of cells called G protein-coupled receptors (GPCRs) to mediate their therapeutic actions. Drugs like caffeine – the stimulant in coffee and tea – bind to these types of receptors to trigger a cascade of effects inside cells to stop a naturally occurring brain chemical from making us feel tired. Caffeine can have other effects due to that cascade of intercellular actions, but such effects are generally mild. Other drugs that aim to treat more serious problems, such as some used to treat depression, can partially alleviate these symptoms but often not without severe side effects. These side effects, which can include weight gain, sleepiness, and dry mouth, occur because medications do not precisely target the GPCRs. Similar side effects due to this lack of specificity plagues most medications that target GPCRs.
Roth and colleagues have been working to overcome this problem over the past several years by harnessing sophisticated and cutting-edge technologies including lipidic cubic-phase x-ray crystallography, cryo-electron microscopy, and ultra-large-scale computational chemistry to determine how drugs bind to and affect the activity of these receptors. Importantly, the researchers have developed new techniques to fully elucidate how drugs might affect signal processes inside cells to create drugs that are more effective.
“Designing drugs to stabilize these specific cell-signaling complexes represents a ‘grand challenge’ for neuropsychiatric drug discovery, as there are currently no FDA-approved medications with the desired signaling profiles,” said Roth, who also holds a faculty appointment at the UNC Eshelman School of Pharmacy. “We will take advantage of our recent innovations in GPCR structural determination to stabilize specific serotonin receptors and identify tens to hundreds of thousands of new candidates for developing better medications.”
He added, “Rapidly acting drugs with antidepressant, anti-anxiety, and anti-addictive potential devoid of disabling side effects do not exist, not even as experimental compounds for use in animals. Creating such compounds would change the way we treat millions of people around the world suffering from these serious and life-threatening conditions.”
This project is sponsored by the Defense Advanced Research Projects Agency (DARPA), which is part of the United States Department of Defense. The views, opinions, and/or findings contained in this material are those of the authors and should not be interpreted as representing the official views, policies, or endorsement of the Department of Defense or the U.S. Government.
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