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Drug Discovery

Targeting RNA’s tertiary structure

Small molecule disrupts RNA motif that’s found in fungus but not humans

by Bethany Halford
October 28, 2018 | A version of this story appeared in Volume 96, Issue 43


Structure of small molecule Intronostat B.

When scientists talk about druggable targets, they’re usually referring to proteins. But a new report confirms that RNA’s tertiary structure could also provide a rich vein of druggable biomolecules. Yale University’s Anna Marie Pyle and coworkers reasoned they could come up with druglike molecules by taking aim at the mitochondrial RNA tertiary structure known as self-splicing group II intron. This bit of RNA is essential for respiration in plants, fungi, and yeast, but it doesn’t exist in people or other mammals. The researchers screened a library of 10,000 compounds and found 16 that prevented the piece of RNA from working. Some of those molecules share common structural elements, which suggests they may have the same mechanism of action. The team then tweaked the basic skeleton of these compounds hoping to improve their potency and pharmacological properties. The most potent compound they made, which they dubbed intronistat B, fights the pathogen Candida parapsilosis, with antifungal activity that’s comparable to that of amphotericin B (Nat. Chem. Biol. 2018, DOI: 10.1038/s41589-018-0142-0). “Given the unique RNA metabolism of plants, fungi, and yeast, our results demonstrate that RNA targeting may provide a much needed approach for developing therapeutics against eukaryotic pathogens,” the researchers note.


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