Plenary Pioneers, Part 2: On the Right Track: How the Many Paths of GPCRs Could Lead to Treatment Breakthroughs

At ENDO 2021, the first time the Endocrine Society’s annual conference has gone all-virtual, a live Presidential Plenary on March 20 will feature a pair of presentations on the latest developments in basic tissue engineering. Nobel Prize winner Brian Kobilka, MD, talks to Endocrine News about his session, “Structural Insights into G Protein-Coupled Receptor Activation: Implications for Drug Discovery.”

Taking place from March 20 to 23, 2021, ENDO 2021 will offer more than 70 live sessions in addition to another 70 on demand sessions via a state-of-the-art digital platform that also accommodates interactivity among participants as well as networking opportunities and even a virtual exhibit hall.

One live session you won’t want to miss is “The Impact of Basic Tissue Engineering and the Basic Biology of GPCRs in Emerging Therapies,” a presidential plenary on March 20, from 11:00 am to 12:00 pm.

Comprising two talks, this plenary showcases pioneering advances in therapy with “Synthetic Hydrogels as Engineered Niches in Regenerative Medicine,” by Andrés J. García, PhD, executive director, Parker H. Petit Institute for Bioengineering and Bioscience and George W. Woodruff School of Mechanical Engineering Regents’ Professor at the Georgia Institute of Technology in Atlanta, Ga., and “Structural Insights into G Protein-Coupled Receptor Activation: Implications for Drug Discovery,” by Brian Kobilka, MD, professor and chair of molecular and cellular physiology at the Stanford University School of Medicine, Stanford, Calif., and co-recipient of the 2012 Nobel Prize in Chemistry for his work with GPCRs.

In this second of two articles highlighting this plenary session, Endocrine News spoke to Kobilka about why G protein-coupled receptors (GPCRs) are such vital conduits for pharmaceuticals, why drug discovery has been so frustrating through the years, and what attendees can expect from his session.

GPCRs and Drug Discovery

Having been a pioneer in the structural biology of GPCRs, Brian Kobilka, MD, is particularly well suited to share structural insights into GPCR activation. During his presentation, he’ll provide an overview of what GPCRs are followed by what has been learned about and from their structures since his trailblazing work more than a decade ago.

As is well known by now since their discovery several decades ago, the GPCR family represents the largest and most versatile group of cell surface receptors, carrying messages from outside a human cell to its interior via the cell membrane. GPCRs, in fact, handle up to 80% of signal transduction across cell membranes.

“The majority of the body’s responses to hormones and neurotransmitters are mediated by GPCRs,” Kobilka says. Cloning of GPCRs, beginning in the 1980s, revealed a common architecture consisting of seven transmembrane helices connected by extracellular and intracellular loops; however, understanding how these helices were arranged in three dimensions would require another 20 years of research by Kobilka and others in the field.

“During my residency in internal medicine, I became very interested in intensive care medicine and in particular the drugs frequently used there. As it turned out, many of these drugs targeted GPCRs. If you wanted to specialize in intensive care medicine at the time, there were essentially two specialties: cardiology or pulmonary medicine,” he explains.

“During my residency in internal medicine, I became very interested in intensive care medicine and in particular the drugs frequently used there. As it turned out, many of these drugs targeted GPCRs. If you wanted to specialize in intensive care medicine at the time, there were essentially two specialties: cardiology or pulmonary medicine.” – Brian Kobilka, MD, professor and chair of molecular and cellular physiology, Stanford University School of Medicine, Stanford, Calif.

Kobilka opted to do a postdoctoral fellowship at Duke University because it offered not only a strong clinical cardiology program but also opportunities to do research. Under the mentorship of Robert Lefkowitz, MD, a pioneer in the field of GPCRs and later Kobilka’s Nobel Prize co-recipient, he began studying the b₂-adrenergic receptor.

All Pathways Lead to GPCRs

Although his fascination developed incidentally, it took hold. “GPCRs are important drug targets because of their central role in normal homeostasis,” he says. As a result, more than a third of our current pharmaceutics are directed at them. So why, then, have only a very small percentage of the more than 800 known GPCRs been targeted for therapeutics?

This is precisely the tangle Kobilka hopes to start to unravel in his presentation: “I’m going to talk about challenges in drug discovery for GPCRs — why it’s been difficult to obtain drugs that are highly selective and highly efficacious with few side effects. I’ll provide some structural insights into why there have been these challenges and what are the major challenges we face in drug discovery,” he explains.

Clearly, if researchers understand the basic physiology and pathophysiology of GPCRs, they’ll be better equipped to develop new therapeutics that activate or inhibit the receptors, accordingly. So, in 2007 when Kobilka and his colleagues determined the first crystal structures of a GPCR for hormones or neurotransmitters, the search for how these receptors work and how they signal became possible.

“[T]here are nine adrenergic receptors, and their binding pockets for adrenaline are, in some cases, identical or very similar. As a result, finding drugs that are selective for one over the other has been challenging. Another is that these receptors often signal through more than one pathway, with one pathway providing beneficial effects of the drug while another pathway might lead to adverse effects.” – Brian Kobilka, MD, professor and chair of molecular and cellular physiology, Stanford University School of Medicine, Stanford, Calif.

In terms of particular challenges, Kobilka says that there are many closely related subtypes — subfamilies within the larger GPCR family. “For example, there are nine adrenergic receptors, and their binding pockets for adrenaline are, in some cases, identical or very similar,” he explains. “As a result, finding drugs that are selective for one over the other has been challenging. Another is that these receptors often signal through more than one pathway, with one pathway providing beneficial effects of the drug while another pathway might lead to adverse effects.”

This better understanding of the complexities of GPCR signaling is what Kobilka hopes the audience takes away from his presentation and which will perhaps soon lead to breakthroughs in drug design.

Horvath is a freelance writer based in Baltimore, Md. She wrote Part I of this series in the January issue.