There is a 3D print of a spike protein of the virus that causes COVID-19. The virus can enter and cause damage in human cells. The red and blue spikes on the virus surface enable it to enter and cause disease. Credit: National Institute of Health.
The coronaviruses genome looks like a tangle of spaghetti or tangled yarn to the untrained eye. The complex shapes that RNA takes on as it folds could have therapeutic potential in the fight against COVID-19.
The study will be published in the journal Science Advances.
"These are the first molecules that target the virus'sRNA specifically, so it's a completely new mechanism in that sense," Hargrove said.
That's good news, even more than 18 months into the epidemic. We have vaccines to prevent COVID-19, but effective drugs to help people survive and recover are limited.
In some parts of the world, the virus is waning, but it's not gone away in others. Many of the world's eight billion people remain vulnerable to infections because of the lack of easy access to vaccines.
The coronaviruses need to break in, deliver its genetic instructions in the form ofRNA, and hijack the body's machinery to build new copies of itself. The cell becomes a factory for the creation of the virus's genetic code and its ability to spread.
The only antiviral drugs for COVID-19 that have been FDA-approved or are in line for approval are remdesivir, molnupiravir and Paxlovid. Hargrove and his colleagues are different. They've identified the first molecule that targets the viral genome itself, and not just the linear sequence of A's, C's, G's and U's, but the complex three-dimensional structures theRNA strand folds into.
When the first terrifying hints of the pandemic started to make headlines, the team including Hargrove, Blanton Tolbert from Case Western Reserve University and Gary Brewer and Mei-Ling Li from Rutgers were already investigating potential drug candidates to fight another RNA virus.
They found a class of small molecule called amilorides that can bind to the folds of the virus's genetic material and cause it to malfunction.
To see if the same compounds could be used against coronaviruses, they tested 23 amiloride-based compounds against another coronaviruses. They found three compounds that reduced the amount of virus in monkey cells without causing damage to their host cells. They had greater effects at higher doses. The researchers found the same results when they tested the molecules on cells that had been exposed to the COVID-19 virus.
The molecule stopped the virus from building up by binding to a site in the first 800 letters of the viral genome. Most of the stretch ofRNA doesn't code for the proteins, but drives their production.
Researchers are working on new ways to cure COVID-19 infections, using molecules that bind to three-dimensional folds in the virus's genetic material. Credit: Duke University.
The region folds in on itself to form bulges and structures. The researchers were able to identify where the chemical compounds were binding using a technique called nuclear magnetic resonance spectroscopy.
The researchers are trying to figure out how these compounds stop the virus from replicating.
The field of using RNA as a drug target is still in its early stages. There is a reason for that. It's hard to design molecules that can interact with them in specific ways because they bounce around a lot more than their counterparts.
The binding pocket may not be present most of the time.
The ribosomes of the human host are the ones that contain 85% of theRNA in aninfecting cell. "There's a lot of competition," he said.
Hargrove is hopeful. The FDA approved the first small-molecule drug that works by binding to non-ribosomal RNA directly, rather than proteins, to treat people with a devastating disease. "It's not impossible, even though there are lots of challenges," Hargrove said.
There is a patent pending on the method. They want to modify the compounds to make them more potent, and then test them in mice to see if this could be a viable drug candidate.
The researchers say that this isn't the first time that coronaviruses have caused an outbreak. The same family of viruses was responsible for the emergence of the Severe Acute Respiratory Syndrome (SRS) in China in 2002 and the Middle East Respiratory Syndrome (MEAS) in Saudi Arabia in 2012
The researchers found that the loops and bulges of the RNA in the coronaviruses they identified have remained essentially the same as they have always been. That means they might be able to fight more than just the COVID-19 virus.
When the next Pandemic hits, we'll be better prepared because we have more antivirals. Fighting resistance would be a benefit if there were more drugs on hand. Viruses change over time. It would be less likely that the virus could develop resistance to all of them at the same time if drugs were combined with different mechanisms of action.
"This is a new way to think about the effects of antivirals on the human body," Hargrove said.
The authors of Amilorides Inhibiting SARS-CoV-2 Replication in the lab. Science.org has a DOI of/10.1126/sciadv.abl6096.
Science Advances has journal information.
The coronaviruses's tangled strands ofRNA could offer new ways to treat people who get infections.
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