Science Concentrates
Glycosylation modification (stick figure)
STRUCTURAL BIOLOGY
Two views of elusive diabetes drug target Studies detail GLP-1 receptor interactions Two research teams have determined structures of glucagon-like peptide-1 (GLP-1) receptor bound to peptide ligands, feats that could aid the discovery of new drugs for diabetes and other conditions. Binding of the peptide hormone GLP-1 activates the receptor, causing cell signaling that helps regulate glucose metabolism and insulin release from the pancreas. GLP-1 itself is rapidly broken down in the body and therefore can’t be used as a drug. But several peptides that mimic GLP-1’s activity and have better stability and longevity are approved type 2 diabetes drugs. These include albiglutide, dulaglutide, exenatide, liraglutide, and lixisenatide. Researchers are also investigating activators and deactivators of the receptor as treatments for obesity, endocrine and cardiovascular disorders, and neurodegeneration. Because all the approved GLP-1 mimics are costly to produce and must be injected, scientists are exploring smaller peptides or other GLP-1-mimicking small molecules that might be cheaper to make and that patients might take orally. But those smaller agents have been hard to identify and develop, and none has yet been approved. The new structures reveal peptide-receptor interactions that might now help drug designers develop small-molecule drugs.
GLP-1 receptor extracellular domain
GLP-1 peptide (stick figure)
GLP-1 peptide (red)
GLP-1 receptor Georgios Skiniotis of transmembrane the University of Michigan domain Medical School, Brian K. Kobilka of Stanford University School of Medicine, and coworkers, including researchers at the drug discovery company ConfometRx, determined the cryo-electron Marshall structure microscopy structure of a rabbit GLP-1 receptor bound to fullbilka structure reveals length human GLP-1 interactions of the Antibody peptide and Gs, a G full-length peptide fragment protein that transnot included in mits receptor signals Gs protein the Marshall (Nature 2017, DOI: 10.1038/ structure but that nature22394). It has 3.9-Å the latter is at highresolution at the peptide-reer resolution and ceptor and receptor-Gs shows interactions in interfaces. greater detail. Fiona H. Marshall and coMarshall says she Skiniotis-Kobilka structure workers at Heptares Therapeubelieves that the complex tics obtained a 3.7-Å-resolution X-ray crystal network of peptide-receptor interactions structure of a mutationally stabilized human “would be very difficult to mimic with a GLP-1 receptor bound to a shortened and small-molecule drug, which would be the modified human peptide (Nature 2017, DOI: ideal if you wanted an oral therapy for diabe10.1038/nature22800). tes.” But her group did use information from The nature of GLP-1 peptide-receptor inits structure to design three GLP-1 peptide teractions “has been unknown and very diffi- mimics that are 10 residues long, one-third cult to model with any accuracy,” says GLP-1 the length of the native hormone. Other receptor expert Patrick Sexton of Monash small-molecule mimics may be out there as University. He notes that the Skiniotis-Kowell, she notes.—STU BORMAN
NEUROSCIENCE
Some antidepressants, such as fluoxetine (Prozac), work by preventing neurons from vacuuming up the neurotransmitter serotonin from the gaps between brain cells—a process called reuptake. By doing so, the drugs increase levels of serotonin in the brain and thus elevate mood. An international team of researchers reports a small molecule that can do something similar for endocannabinoids, a family of greasy signaling molecules that our bodies produce to regulate myriad functions, including appetite, mood, and inflammation (Proc. Natl. Acad. Sci. USA 2017, DOI: 10.1073/ pnas.1704065114). The active ingredient in
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C&EN | CEN.ACS.ORG | JUNE 12, 2017
marijuana, tetrahydrocannabinol (THC), turns on the same receptors targeted by endocannabinoids. The work points to a possible new approach to regulating endocannabinoid signaling through small-molecule drugs, says Jürg Gertsch of the University of Bern, who led the team. Other endocannabinoid reuptake inhibitors exist, but they have had a downside: They shut down enzymes responsible for degrading endocannabinoids and other lipids (see page 5), so inhibiting the proteins affects more than just the endocannabinoid system, Gertsch says.
To avoid targeting these enzymes, Gertsch and colleagues screened a library of 634 compounds based on an endocannabinoid-like molecule from the plant Echinacea purpurea that lacks features common to lipids synthesized by our bodies. The winner, WOBE437, potently blocked endocannabinoid reuptake but did not inhibit the degradation enzymes. In mice, WOBE437 increased endocannabinoid levels and had anti-inflammatory and antianxiety effects. The scientists want to design a probe based on WOBE437 to identify the protein transporters involved in reuptake.—MICHAEL TORRICE
CREDIT: ADAPTED FROM NAT U RE
Inhibiting endocannabinoid reuptake
