Science Concentrates MATERIALS
The mechanistic target of rapamycin (mTOR) is an important protein complex in many cell signaling pathways, and could be a new drug target for treating depression.
DRUG DISCOVERY
New possible target for rapid antidepressants found Navitor molecule boosts mTORC1 activity, reduces depression symptoms in rats People with depression have to take currently available antidepressants for months before they start to get relief from their symptoms. But scientists are on the hunt for new, fast-acting antidepressants. For example, ketamine can improve symptoms in a matter of hours, but comes with undesirable side effects such as hallucinations and out-of-body experiences. So researchers want to understand which cellular pathways ketamine turns on and off to find new antidepressant drug targets that don’t lead to acute psychiatric side-effects. Scientists at Yale University and Navitor Pharmaceuticals think they have a compound with potential. The molecule boosts activity of an important signaling hub in brain cells and rapidly alleviates symptoms of depression in rats. The team reported data on the molecule on Nov. 14 at the Society for Neuroscience annual meeting in Washington, D.C. When ketamine binds to receptors on the surface of neurons, one of the downstream signaling protein complexes it activates is mTORC1. This protein complex is present in many cells in the body and regulates cell growth and metabolism in response to nutrient availability. One hallmark of depression is reduced mTORC1 activity in the brain, says Navitor CEO George P. Vlasuk, but finding a way to boost that activity has been difficult. Navitor’s collaborators discovered a new way to turn up mTORC1 activity—a nutrient-sensing pathway mediated
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C&EN | CEN.ACS.ORG | NOVEMBER 27, 2017
through a protein called sestrin2 (Science 2016, DOI: 10.1126/science.aab2674). The company then developed NV-5138, a small molecule that binds to sestrin2, which then releases its hold on mTORC1 and, as a result, activates the complex. Navitor’s patent for NV-5138 is still pending, so the structure has not yet been published. Ronald S. Duman of Yale University, led the effort to test the new compound as an antidepressant. In rats with depressionlike symptoms, an oral dose of NV-5138 rapidly penetrated the brain and, within one hour, activated mTORC1 in the prefrontal cortex, a brain region affected in depression. And, similar to ketamine, NV-5138 boosted the density and strength of connections between neurons in the prefrontal cortex. The small molecule relieved some symptoms of depression in rats, such as a lack of interest in a treat (sugar water), and the effects of a single dose lasted up to 7 days. Lisa Monteggia, a neuroscientist at the University of Texas Southwestern Medical Center, points out that mTORC1 interacts with many cellular processes, so directly activating it could still trigger side effects. Vlasuk agrees. “This is the first small molecule direct activator of mTORC1 that’s been described,” he says. “We want to know as much about it as we can.” The next step for Navitor scientists is to assess NV-5138’s safety and efficacy in humans, he says. The company plans to begin phase I trials in the first half of 2018.—EMMA HIOLSKI
The world’s oceans contain more than 4 billion tons of uranium, an amount that could supply fuel for nuclear power production for centuries. The trick is how to harvest the metal ions, which occur at a dilute 3.3 ppb in the vast and deep blue sea. Chemists have long been developing polymeric materials that selectively absorb uranium, gold, and other valuable metals from seawater. For uranium, researchers have focused on sorbent mats made from poly(amidoxime)s in which the nitrogen-oxygen functional groups in the polymers selectively bind uranium ions. In a new study, Alexander S. Ivanov of Oak Ridge National Laboratory (ORNL) and coworkers report a nuance in this chemistry: poly(amidoxime)s actually bind vanadium ions better than uranium ions. This observation could lead to developing better materials for plucking uranium out of seawater, Ivanov says, but also help in efforts to mine the oceans for metals like vanadium and lithium, which are used in batteries, rather than using environmentally destructive surface mining (Nat. Commun. 2017, DOI: 10.1038/s41467-017-01443-1). By using a combination of titration, X-ray spectroscopy, and computer simulation, ORNL researchers in collaboration with Lawrence Berkeley National Laboratory and UC Berkeley found that the cyclic imide-dioxime units in poly(amidoxime)s preferentially bind V5+ over UO22+. They also found that linear amidoxime units in the polymers don’t bind V5+ but do bind UO22+. This knowledge should help researchers design polymers for more efficient capture of uranium, vanadium, and other metals.—STEVE RITTER
CR E D I T: S H UT TE RSTOC K
New surprise for metalbinding polymer
