Break the “clutch” of COVID-19 and stop its spread

Jupiter, Florida-September 30, 2020-Scripps Research chemist Dr. Matthew Disney and colleagues bind and destroy the so-called “frameshift element” of the pandemic coronavirus in human cell research .. A frame shifter is a clutch-like device that is needed to make a new copy of itself after a virus infects a cell.

“Our concept was to develop a major drug that could break the COVID-19 clutch,” says Disney. “It does not allow gear shifts.”

The virus spreads by entering cells and mass-producing new infectious copies using the cell’s protein-building mechanisms. Those genetic materials must be compact and efficient for entry into cells.

Pandemic coronaviruses remain small by encoding the multiple proteins needed to build a new virus with a single genetic string. A frameshift element, such as a clutch, suspends a cell’s protein-building engine, called the ribosome, slips into another gear or reading frame, and then restarts protein assembly to produce different proteins from the same sequence. To do.

However, it is not easy to allow the drug to stop the process. The virus that causes COVID-19 encodes its gene sequence into RNA, the chemical cousin of DNA. Although it has historically been extremely difficult to combine RNA with orally administered medicines, Disney’s group has been developing and improving tools to do so for over a decade.

A scientist’s report entitled “Targeting the SARS-CoV-2 RNA Genome with Small Molecular Binders and Ribonuclease Targeted Chimera (RIBOTAC) Degrading Factors” was published in the journal on September 30. ACS Central Science..

Disney emphasizes that this is the first step in a long process of sophistication and research going forward. Still, the results show the feasibility of directly targeting viral RNA with small molecule drugs, Disney says. He adds that their study suggests that other RNA viral disorders may ultimately be treated by this strategy.

“This is a proof-of-concept study,” says Disney. “We put a frameshift element into the cell and showed that the compound binds to and degrades the element. The next step is to do this throughout the COVID virus and optimize the compound.”

The Disney team worked with Dr. Waltermos, an assistant professor at Iowa State University, to analyze and predict the structure of the molecule encoded by the viral genome and look for its vulnerabilities.

“By combining a predictive modeling approach with tools and technologies developed at Disney Labs, we can quickly discover the draggable elements of RNA,” Moss says. “We are using these tools to accelerate progress towards the treatment of COVID-19, as well as many other illnesses.”

Scientists have focused on the frameshift element of the virus. This is because it has a stable hairpin-shaped segment that acts like a joystick that controls protein construction. They predicted that binding a joystick to a compound like a drug would defeat the ability to control frameshifts. Since the virus needs all the proteins to make a complete copy, blocking the shifter and distorting even one of the proteins should theoretically stop the virus completely.

Using a database of RNA-binding chemicals developed by Disney, we found 26 candidate compounds. Further testing with different variations of frameshift structures revealed three candidates that successfully tied them all together.

Disney’s team in Jupiter, Florida, immediately set out to test compounds in human cells with a frameshift element of COVID-19. These tests revealed that one, C5, had the most significant dose-dependent effect and did not bind to unintended RNA.

They then went a step further and designed the C5 compound to carry RNA editing signals that specifically disrupt viral RNA into cells. With the addition of the RNA editor, “these compounds are basically designed to eliminate the virus,” Disney says.

Cells need RNA to read DNA and build proteins. Cells have a natural process of removing cells from RNA after using them. Disney used this waste treatment system chemically to chew COVID-19RNA. His system is called RIBOTAC and stands for “ribonuclease target chimera”.

Disney says adding RIBOTAC to a C5 anti-COVID compound increases its potency by a factor of 10. More work awaits this to become a successful drug for clinical trials. He says there’s a lot to learn because this is a whole new way to attack viruses.

“We wanted to publish as soon as possible to show the scientific community that the COVID RNA genome is a medicinal target. We have encountered many skeptics who think that small molecules cannot target RNA,” Disney said. say. “This is another example of wanting RNA to be at the forefront of modern medicine as a drug discovery target.”

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