Candida sp. infections are among the most serious diseases, especially among immunocompromised patients, leading to high rates of morbidity and mortality.
Researchers from the Howard Hughes Medical Institute, showed that Candida species’ RNA de novo structures can be targeted, resulting in the inhibition of group IIB intron splicing in vitro and in vivo and with no toxicity in human cells.
These compounds showed to be growth inhibitors of Candida parapsilosis, with an antifungal activity comparable to that of amphotericin B. These findings may assist in the rational development of novel therapies in fungal diseases.
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.
Reference: Olga Fedorova, G. Erik Jagdmann Jr., Rebecca L. Adams, Lin Yuan, Michael C. Van Zandt, Anna Marie Pyle. Small molecules that target group II introns are potent antifungal agents. Nature Chemical Biology (2018).