Science Concentrates PHARMACEUTICALS
An opioid minus major side effects Fluorinated compound is active only in areas of inflammation computationally model what the extra protons might be doing to the binding behavior of opioids. They found that the lower pH greatly improved the opioids’ binding. “We then asked the question, Can you make a compound that acts only in the inflamed environment and not in the normal
NFEPP has a pKa of 6.8, so it’s protonated only in the low-pH environment of injured or inflamed tissue. In the brain, however, NFEPP isn’t protonated and is therefore inactive, Stein says. Grégory Scherrer, who studies opioids and molecular mechanisms of pain at Stanford University, wonders F O O about NFEPP’s mechanism of action. Stein’s team provides N N N N evidence that the compound acts predominantly on opioid receptors present on pain neurons at the site of injury, he Fentanyl NFEPP points out. But they don’t show environment in the brain,” where many how NFEPP modifies the function of those side effects originate? Stein explains. They pain neurons. Does it reduce excitability settled on a fluorinated version of fentanyl of cells that signal pain to the brain? If so, called NFEPP. The addition of a fluorine what ion channels are involved? he asks, atom draws electron density from the adding, “I’m excited to follow the authors’ compound’s tertiary amine, which must be future work and to have answers to these protonated for the compound to be active. questions.”—BETHANY HALFORD
DRUG DISCOVERY
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Small molecule helps fix rare-disease mutation Sobetirome partially makes up for lost function of mutated gene in ‘Lorenzo’s Oil’ disease Researchers have identified a small organic molecule that may help fix the genetic defect that causes X-linked adrenoleukodystrophy (X-ALD), the rare disease featured in the 1992 movie “Lorenzo’s Oil.” X-ALD kills boys diagnosed in early childhood and has an adult form that impairs nervous system function progressively. The cause is an inherited mutation in the gene for ABCD1, a protein that transports very long-chain fatty acids (VLCFAs) to cell vesicles called peroxisomes, which break VLCFAs down. The mutation allows VLCFAs to overaccumulate in the brain and spinal cord, where they destroy myelin sheaths on brain and spinal cord nerve cells by an unknown mechanism. Director of chemical biology Thomas S. Scanlan and coworkers at Oregon Health
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C&EN | CEN.ACS.ORG | MARCH 6, 2017
& Science University show that sobetirome, a small molecule they discovered earlier, reduces VLCFA levels in the brains of X-ALD-affected mice (Endocrinology 2017, DOI: 10.1210/en.2016-1842). The compound works by activating the gene for ABCD2, a sibling of ABCD1 that does not contain an inherited mutation, partially restoring normal VLCFA breakdown. As depicted in the movie, the parents of Lorenzo Odone, who was six when diagnosed with X-ALD, discovered Lorenzo’s oil, an extract that inhibits VLCFA synthesis.
Lorenzo’s oil, made by Nutricia, is an experimental treatment for X-ALD. Sobetirome (structure shown) has had encouraging results for treating the disease in mice.
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Sobetirome The product is available commercially but is still experimental. Lorenzo lived much longer than expected but died at age 30. Scanlan and coworkers now report that sobetirome, which activates the thyroid hormone receptor and can reach the brain, lowered brain VLCFAs 15 to 20% in X-ALD-affected mice after 12 weeks’ oral dosing. Is that sufficient to be therapeutic? Only clinical trials will tell. Sobetirome caused few side effects in an earlier human clinical trial for lowering cholesterol. NeuroVia, which Scanlan helped found, is developing sobetirome clinically to treat X-ALD, and FDA has given the compound orphan drug status. Stephane Savary of the University of Bourgogne, who cloned the gene for ABCD2 and studied sobetirome’s effects, comments that the study’s “results in mice are really encouraging and deserve a clinical trial.”—STU BORMAN
CREDIT: NUTRICIA
When given to rats, a new opioid relieves their pain but doesn’t cause the negative side effects typically associated with this class of analgesic, such as addiction, respiratory depression, and constipation (Science 2017, DOI: 10.1126/science.aai8636). “These things are big problems when we treat patients for long periods of time with opioids,” says Christoph Stein, a professor of anesthesiology and critical care medicine at the Free University of Berlin, who led the research. Stein’s group has spent more than 25 years studying opioid receptors on neurons outside the brain and spinal cord. These receptors, he says, become more active at sites of injury or inflammation. Knowing that pH is lower at such sites and that therefore more protons are floating around, Stein teamed up with Marcus Weber at Zuse Institute Berlin to
