Bulging, looping, and twisting, RNA molecules present distinctive three-dimensional shapes, which presumably contain nooks and crannies into which small molecules can nestle, raising expectations that RNA molecules could be “druggable.” Yet few RNA-targeting drugs have been approved to fight human disease. In hopes of developing drugs that could settle into highly structured RNA molecules, scientists based at Yale have devised a new screening technique. This technique, which combines high-throughput processing, structure-activity relationship (SAR) analysis, and lead optimization, helped the Yale team led by biochemist Anna Pyle, Ph.D., the Sterling professor of molecular, cellular and developmental biology, identify potential antifungal drugs.

The team identified small molecules that would inhibit a group of large, self-splicing ribozymes found in bacteria, plants, and fungi—but not found in mammals. These RNA molecules have an elaborate structure that contains tiny, solvent-accessible pockets for a small molecule drug to bind with the larger molecule.

Details of this work appeared October 15 in the journal Nature Chemical Biology, in an article titled, “Small molecules that target group II introns are potent antifungal agents.” The group II intron is a self-splicing mitochondrial RNA tertiary structure. It is absent in vertebrates but essential for respiration in plants, fungi, and yeast.

The researchers also chose this RNA structure because of its crucial role in the metabolism of opportunistic fungal organisms that are especially problematic for patients with compromised immune systems, including patients with implanted devices, neonatal patients, and cancer patients.

“Here we show that this RNA can be targeted, resulting in high-affinity compounds that specifically inhibit group IIB intron splicing in vitro and in vivo and lack toxicity in human cells,” the authors of the article wrote. “The compounds are potent growth inhibitors of the pathogen Candida parapsilosis, displaying antifungal activity comparable to that of amphotericin B.”

“Our work establishes that RNA is 'druggable,' and that refractory pathogens such as pathogenic fungi and drug-resistant bacteria can be attacked by targeting their unique RNA repertoire,” Dr. Pyle adds. “It demonstrates that the burgeoning landscape of functional RNA elements contains a wealth of potential targets that can be modulated by small molecules, opening a new frontier in molecular pharmacology.”

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