Michelle Li

Yale researchers have devised a new way to fight infections, using small-molecule drugs to target RNA, instead of the more common drug targets — proteins.

The recent study, which was published in the journal Nature Chemical Biology on Oct. 15, found that it is possible to target complex RNA molecules before they are translated into protein, supporting the development of a new generation of drugs to treat fungal infections, including yeast infections, by hijacking the pathogens’ RNA. 

“For us, this study is largely grounds for illustrating what can be done with RNAs. The inhibitors we found in this first round are as good as the standard of care,” said Anna Pyle, Sterling Professor of Molecular, Cellular and Developmental Biology. “We weren’t necessarily trying to find a potential drug candidate — we were shocked to find such a potent compound.”

The study will impact not only the field of molecular and cellular biology but also pharmacology. Amphotericin B is one of the therapeutics currently used for patients with yeast infections. But Rebecca Adams, a postdoctoral fellow in the Pyle Lab and co-author on the study, explained that pathogens are becoming increasingly resistant to the drugs currently on hand.

According to the study, the compounds the researchers used were equally potent to amphotericin B. At similar concentrations, both drugs were similarly effective at killing yeast.

“Before, people were hesitant to consider RNA for drug design. We have shown that people can … create a new generation of drugs for larger, more complicated RNA structures,”  said Olga Fedorova, a research specialist in the Pyle Lab and a study co-author.

The chemical compounds used in the study targeted a specific RNA structure found in pathogenic yeasts called group II autocatalytic introns. Introns are portions of RNA that are cut out and discarded before the RNA is translated into a protein.

“If we can prevent the RNA from tying up into a knot, then the intron would not be spliced out. By messing up the cutting process, you’re preventing the production of certain proteins,” Adams said.

The researchers’ method — screening through hundreds of thousands of compounds to see which one would actually inhibit the RNA — is similar to what researchers have done for close to a century to target proteins, explained Pyle. But prior to Pyle’s study, no one had ever used this method for RNA targeting.

“Because we used a classical approach, it means that you don’t have to come up with an entirely new way to find drugs for RNA. We’ve shown that drugging RNA is not different from anything we’ve done before,” she said.

Yeast cells are very similar to human cells, Adams explained, but fortunately, yeasts have group II introns, which are a central component of their respiration, while humans do not. In targeting these introns, the team was able to inhibit growth of Candida parapsilosis — a fungal species linked to post-operative infections — without harming human cells.

In the study, researchers proved that the compounds exclusively targeted the RNA itself — and were responsible for the death of the yeast cells.

The researchers used the work of molecular biophysics and biochemistry professor Ronald Breaker as the foundation for their study, Pyle said. Breaker’s lab discovered a special class of RNA molecules called riboswitches whose sole job is to bind small molecules.

According to Pyle, her lab has been studying RNA tertiary structures for decades — since it first opened in 1992 — and was the first to solve the structure of the group II intron in 2008. When the researchers saw the molecule for the first time, they recognized immediately that it had many of the features of a protein enzyme and therefore could be modulated in a similar way, Pyle said.

Pyle said that moving forward, the research team plans to scan a larger library of compounds to find more examples of RNA-targeting compounds.

“Nobody knows about the common attributes of RNA-targeting compounds, so we want more examples,” Pyle said.

Michael Van Zandt, president and CEO of New England Discovery Partners, a Connecticut-based chemistry research company, and a co-author of the study, said that he is hopeful for the future of RNA as a drug target. He noted that he expects the field to grow dramatically in the next 10 to 15 years.

“We have some other compounds specifically for RNA not in this paper … and are certainly in the process of writing another grant that will involve Yale faculty as well,” Van Zandt said.

New England Discovery Partners currently has 17 experienced synthetic organic chemists working for them on drug discovery projects for pharmaceutical companies.

Gabriel Klapholz | gabriel.klapholz@yale.edu .