Recent years have seen an explosion of disease-relevant research on G-protein coupled receptors (GPCRs). Hot topics include strategies for targeting GPCRs therapeutically, and understanding the mechanisms of biased agonism. A number of distinguished speakers will present their latest GPCR research at the GPCR Colloquium at the “American Society for Pharmacology and Experimental Therapeutics” meeting.
In the phenomenon of biased agonism in GPCRs, a biased ligand activates one signaling pathway without activating another. “Biased agonism represented a paradigm shift,” says Robert Lefkowitz, M.D., professor of chemistry at Duke University and winner of the 2012 Nobel Prize in Chemistry with his colleague and former post-doc Brian Kobilka of Stanford University for their seminal work on 7-transmembrane domain GPCRs.
“Much to our total surprise, we realized that an agonist could stimulate one pathway—G proteins or the arrestins—without stimulating the other. It was a realization that this system could not only turn off G protein signaling, but also establish signaling pathways on its own.”
In addition to the development of GPCR research and biased agonism, Dr. Lefkowitz also plans to unveil some new results of a collaboration with Kobilka’s lab, in which they are trying to work out the molecular mechanisms of biased agonists. “We’re using a variety of structural approaches, including x-ray crystallography, to get at the mechanisms of biased agonists.”
Indeed, the importance of biased agonism in GPCR drug discovery is the work of one of Dr. Lefkowitz’ former post-docs, Jonathan Violin, Ph.D., now head of biology at Trevena. He will discuss how Trevena is using receptor bias for clinical development of pain therapeutics. They are focused on using biased ligands to separate “on-target adverse effects,” or adverse effects presumed inseparable from a drug’s pharmacology, from the drug’s intended therapeutic effects.
For example, Trevena recently discovered an analgesic drug targeting the mu-opioid receptor whose signaling mechanism partly resembles that of morphine, yet differs in that it does not engage beta-arrestins—and therapeutically shows reduced adverse effects of respiratory suppression and opioid-induced constipation.
“We are engaging the very well precedented and very valuable analgesia of this target, but hopefully in a safer and more tolerable fashion, by more precisely tuning in the kinds of intracellular signals that we desire,” says Dr. Violin.
He notes the value of beginning with known targets and signaling mechanisms, and then working to understand the mechanisms of biased ligands of these targets. “What we think is happening with biased ligands is that we are stabilizing a subset of conformations associated with the active pharmacological entity or entities,” he says. In other words, a biased ligand activates only a subset of the different signaling pathways and in vivo pharmacological responses that they normally observe with the full agonist.
“To us, that’s part of the value in our approach,” he says, “that we can take targets for which we know a lot about their clinical benefits or clinical risks, and dissect those so that we don’t have to lay out completely new biological pathways.”