Small molecules that target group II introns are potent antifungal agents

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


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Antifungal Agents / chemistry*
  • Antifungal Agents / pharmacology*
  • Candida parapsilosis / drug effects
  • Candida parapsilosis / genetics
  • Candida parapsilosis / growth & development
  • Electron Transport Complex IV / genetics
  • HEK293 Cells
  • High-Throughput Screening Assays / methods*
  • Humans
  • Introns / drug effects*
  • Introns / genetics
  • Microbial Sensitivity Tests
  • RNA Splicing / drug effects*
  • RNA, Catalytic / genetics
  • Saccharomyces cerevisiae / drug effects
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae Proteins / genetics
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology
  • Structure-Activity Relationship


  • Antifungal Agents
  • RNA, Catalytic
  • Saccharomyces cerevisiae Proteins
  • Small Molecule Libraries
  • Cox1 protein, S cerevisiae
  • Electron Transport Complex IV