Small molecules target SARS-CoV-2 RNA for destruction to prevent the spread of coronavirus -19

Researchers have designed compounds that target RNA that can disable the replication engine of the pandemic coronavirus.

According to reports, Dr. Matthew Disney, a chemist at the Scripps Research Institute, and his colleagues have developed and created drug-like compounds that combine and destroy the so-called "frame-shifting element" of the COVID-19 virus in human cell research. To prevent virus replication. The frame shifter is a device similar to a clutch. The virus needs to produce new copies after infecting cells.

Disney said: "Our concept is to develop a key lead drug that can break the COVID-19 virus. It does not allow shifting."

The virus spreads by entering the cell, and then uses the cell's protein construction mechanism to create a new infectious copy. Their genetic material must be compact and effective to enter the cell.

The COVID-19 virus keeps its size small by making a string of genetic material encode the various proteins needed to assemble a new virus. The clutch-like frameshift element forces the cell’s protein-building engine (called the ribosome) to pause, slide to a different gear or read the frame, and then restart protein assembly to produce different proteins from the same sequence.

However, getting a drug to stop this process is far from easy. The virus that causes COVID-19 encodes its genetic sequence in RNA (a cousin of DNA). Historically, it has been difficult to combine RNA with oral drugs, but the team led by Disney has been developing and improving this method for more than a decade.

The scientist’s report is titled "Targeting the SARS-CoV-2 RNA genome and targeting the ribonuclease of the chimera (RIBOTAC) degrading enzyme with a small molecule binding agent", which was published in the journal ACS Science Center on September 30.

Disney emphasized that this is the first step in the long process of improvement and research in the future. Even so, the results still show the feasibility of using small molecule drugs to directly target viral RNA. He added that their research suggests that other RNA viral diseases may eventually be treated with this strategy.

Disney said: "This is a proof-of-concept study. We put the frameshift element into the cell, and it turns out that our compound binds the element and degrades it. The next step will be to do this for the entire COVID virus, and then The compound is optimized."

The team led by Disney collaborated with Dr. Walter Moss, assistant professor at Iowa State University, to analyze and predict the structure of the molecules encoded by the viral genome to find its weaknesses.

Moss said: "By combining our predictive modeling methods with the tools and technologies developed by Disney Labs, we can quickly discover the medicable components in RNA. We not only use these tools to accelerate the progress of the COVID-19 virus treatment, but It can also treat many other diseases."

The reason why scientists zeroed out the frameshift elements of this virus is partly because it has a stable hairpin-shaped segment that controls protein construction like a joystick. They predicted that combining the joystick with a drug-like compound should lose the ability to control the frameshift. The virus needs all the proteins to replicate completely, so in theory, interfering with the transferor even deforming one of the proteins should completely prevent the virus from replicating.

They used the RNA-binding chemical entity database developed by Disney and found 26 candidate compounds. Disney said that after further testing of different variants of the frameshift structure, three candidates were found to combine them well.

Disney's research team in Jupiter, Florida quickly set out to test the compound in human cells carrying COVID-19 frameshift elements. These tests show that C5 has the most obvious effect in a dose-dependent manner and does not bind unexpected RNA.

They then further studied the C5 compound to carry an RNA editing signal that caused the cell to specifically destroy the viral RNA. Disney said, "With the addition of the RNA editor, these compounds are designed to essentially eliminate the virus."

Cells need RNA to read DNA and build proteins. After using the cell, the cell has a natural process of removing RNA cells. Disney has chemically used this waste disposal system to remove COVID-19 RNA. Its system name is RIBOTAC, which is an abbreviation for "Chimera Targeting Ribonuclease".

He said that adding RIBOTAC to the C5 anti-COVID compound increased its effectiveness tenfold. Much work remains to be done to make it a drug that can be used in clinical trials. He said that because this is a new method of attacking viruses, there is still a lot to learn.

Disney said, “We hope to publish this article as soon as possible to show the scientific community that the COVIDRNA genome is a drug-curable target. We have met many skeptics who believe that a small molecule cannot target any RNA. This is what we hope will be. Another example of RNA being a drug target at the forefront of modern medical science."

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Source: Xianji.com