Researchers Engineer Drug-Like Compounds that Disable SARS-CoV-2's Replication Engine

Researchers at Scripps Research led by Dr. Matthew Disney have created drug-like compounds that, in human cell studies, bind and destroy the pandemic coronavirus' so-called "frameshifting element" to stop the virus from replicating. The frameshifter is a clutch-like device that the virus needs to generate new copies of itself after infecting cells.

In collaboration with Iowa State University Assistant Professor Walter Moss, the team analyzed and predicted the structure of molecules encoded by the viral genome, in search of its vulnerabilities. They focused 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. They predicted that binding the joystick with a drug-like compound should disable its ability to control frameshifting. 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.

From Dr. Disney's database of RNA-binding chemical entities, they found 26 candidate compounds. Further testing with different variants of the frameshifting structure revealed three candidates that bound them all well, Disney says. Tests done in human cells with COVID-19's frameshifting element revealed one, C5, had the most pronounced effect, in a dose-dependent manner, and did not bind unintended RNA. The team went even further and 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," Disney says.

For more details, read the article in Scripps Research.