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Nat Chem Biol. 2018 Dec;14(12):1073-1078. doi: 10.1038/s41589-018-0142-0. Epub 2018 Oct 15.

Small molecules that target group II introns are potent antifungal agents.

Author information

1
Howard Hughes Medical Institute, New Haven, CT, USA.
2
Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT, USA.
3
New England Discovery Partners, Branford, CT, USA.
4
Howard Hughes Medical Institute, New Haven, CT, USA. anna.pyle@yale.edu.
5
Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT, USA. anna.pyle@yale.edu.

Abstract

Specific RNA structures control numerous metabolic processes that impact human health, and yet efforts to target RNA structures de novo have been limited. In eukaryotes, the self-splicing group II intron is a mitochondrial RNA tertiary structure that is absent in vertebrates but essential for respiration in plants, fungi and yeast. Here we show that this RNA can be targeted through a process of high-throughput in vitro screening, SAR and lead optimization, resulting in high-affinity compounds that specifically inhibit group IIB intron splicing in vitro and in vivo and lack toxicity in human cells. The compounds are potent growth inhibitors of the pathogen Candida parapsilosis, displaying antifungal activity comparable to that of amphotericin B. These studies demonstrate that RNA tertiary structures can be successfully targeted de novo, resulting in pharmacologically valuable compounds.

PMID:
30323219
PMCID:
PMC6239893
[Available on 2019-04-15]
DOI:
10.1038/s41589-018-0142-0

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