Inching closer to extending the approach to humans, researchers seeking to improve a promising strategy for noninvasively controlling cellular activity have reported the design of engineered ion-channels that can be activated by low doses of the FDA-approved anti-smoking drug varenicline. They tested their approach - one based on chemogenetics - in live mice and a monkey. Chemogenetics enables non-invasive chemical control over cell populations in behaving animals; it works through processes involving engineering of macromolecules to interact with previously unrecognized small molecules. To date, efforts to use chemogenetics in live animals have suffered from several setbacks, including lacking effective activating molecules. What's more, existing approaches are not compatible with human therapies; ideally, they should involve receptors potently activated by existing clinically approved drugs. Here, Christopher Magnus and colleagues sought to improve on chemogenetic systems. They developed a new ion channel-based platform for studying cell activation and silencing by chemical compounds. They then examined 44 clinically used drugs to see which best activated many of the mutant channels in their platform. The anti-smoking drug, varenicline, was a strong performer, they say, even at very small concentrations. The researchers modified varenicline to improve its potency, and then tested it as a neuron silencer in neuronal cells, where it was effective. They next administered it in the brains of live mice and in a live rhesus monkey, where Magnus and colleagues reported it affected neurons so as to induce behavioral changes. The work is a proof of principle that the authors' compound/ion channel combination approach can both silence and activate neurons and have a behavioral impact. The authors say their platform will enable translational studies in humans.
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Journal
Science