Engineered RNA-Targeting Compounds Break COVID-19’s Clutch by Disabling SARS-CoV-2’s Replication Engine

The frameshifter is a clutch-like device the virus needs to generate new copies of itself after infecting cells. Viruses spread by entering cells and then using the cells’ protein-building machinery to churn out new infectious copies. Their genetic material must be compact and efficient to make it into the cells. The coronavirus stays small by having one string of genetic material encode multiple proteins needed to assemble new virus. A clutch-like frameshifting element forces the cells’ protein-building engines, called ribosomes, to pause, slip to a different gear, or reading frame, and then restart protein assembly anew, thus producing different protein from the same sequence.

Scientists at The Scripps Research Institute zeroed in on the virus’ frameshifting element, in part, because it features a stable hairpin-shaped segment, one that acts like a joystick to control protein-building. Binding the joystick with a drug-like compound should disable its ability to control frameshifting, they predicted. The virus needs all of its proteins to make complete copies, so disturbing the shifter and distorting even one of the proteins should, in theory, stop the virus altogether. Using a database of RNA-binding chemical entities they had developed, the scientists found 26 candidate compounds. Further testing with different variants of the frameshifting structure revealed three candidates that bound them all well. They quickly set about testing the compounds in human cells carrying COVID-19’s frameshifting element. Those tests revealed that one, C5, had the most pronounced effect, in a dose-dependent manner, and did not bind unintended RNA. The scientists then went further, engineering the C5 compound to carry an RNA editing signal that causes the cell to specifically destroy the viral RNA. With the addition of the RNA editor, “these compounds are designed to basically remove the virus,” according to the scientists.

Cells need RNA to read DNA and build proteins. Cells have natural process to rid cells of RNA after they are done using them. The scientists have chemically harnessed this waste-disposal system to chew up COVID-19 RNA. The system is called RIBOTAC, short for “Ribonuclease Targeting Chimera.” Adding a RIBOTAC to the C5 anti-COVID compound increases its potency by tenfold, found the scientists. Much more work lies ahead for this to become a medicine that makes it to clinical trials. Because it’s a totally new way of attacking a virus, there remains much to learn, according to the scientists. The researchers have emphasized that this is a first step in a long process of refinement and research that lies ahead. Even so, the results demonstrate the feasibility of directly targeting viral RNA with small-molecule drugs, according to the team. Their study suggests other RNA viral diseases may eventually be treated through this strategy.

“Our concept was to develop lead medicines capable of breaking COVID-19’s clutch,” said Scripps Research chemist Matthew Disney, PhD. “It doesn’t allow the shifting of gears.”

“This is a proof-of-concept study,” added Disney. “We put the frameshifting element into cells and showed that our compound binds the element and degrades it. The next step will be to do this with the whole COVID virus, and then optimize the compound.”


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