Coronavirus entangled RNA strands may offer new ways to treat infected people

Before 3D printing of SARS-CoV-2 virus particles, 3D printing of the spike protein of SARS-CoV-2, the virus that causes COVID-19. Peplomers (foreground) allow viruses to invade and infect human cells. In the virus model, the surface of the virus (blue) is covered with a spike protein (red), which allows the virus to invade and infect human cells. Credit: NIH

To the untrained eye, the single-stranded loops, twists, and creases of the RNA that make up the coronavirus genome look like spaghetti or a jumble of tangled threads. But for researchers like Amanda Hargrove, a professor of chemistry at Duke University, the complex shapes that RNA takes when it folds have untapped therapeutic potential in the fight against COVID-19. There is a possibility.

In a study published in the journal on November 26th Science Advances, Hargrove and colleagues identified Chemical substances It can latch into these 3D structures and block the ability of the virus to replicate.

“These are completely new mechanisms in that sense because they are the first molecules with antiviral activity that specifically target viral RNA,” Hargrove said.

Even more than 18 months after the pandemic, that’s good news. Vaccines that prevent COVID-19 are available, but effective and easy-to-administer drugs that help survive and recover after infection remain limited.

The virus has receded in some parts of the world, but cases are still booming in other parts of the world where vaccines are scarce. Also, even in areas with easy access to the vaccine, the hesitation of the COVID-19 vaccine means that many of the world’s 8 billion people remain vulnerable to infection.

To infect cells, the coronavirus must invade, convey its genetic instructions in the form of RNA, hijack the body’s molecular mechanisms, and make a new copy of itself. NS Infected cells Become a virus factory and read the “letter” of 30,000 nucleotides of virus Genetic code Stir the proteins needed for the virus to replicate and spread.

Most antiviral drugs, such as remdesivir, molnupiravir, and paxlobid, which are the only antiviral drugs for COVID-19 that have been or will be approved by the FDA, work by binding to these proteins. However, Hargrove and his colleagues take different approaches. They identified the first molecule to target the viral genome itself. We have identified not only the linear sequences of A, C, G, and U, but also the complex three-dimensional structure in which the RNA strands are folded.

When the first horrifying hints of the pandemic began to become headlines, teams including Hargrove, Blanton Tolbert of Case Western Reserve University, Gary Brewer of Rutgers and Mei-Ling Li Already under investigation A drug candidate that may fight another RNA virus called enterovirus 71, which is a common cause of hand-foot-and-mouth disease in children.

They have identified a class of small molecules called amylolide that can bind to hairpin-like folds of the viral genetic material and throw a wrench into the replication of the virus.

To see if the same compound also works against coronavirus, we first put 23 amiloride-based molecules against another non-fatal coronavirus that causes many common colds. I tested it. They identified three compounds that, when added to infected monkey cells, reduce the amount of virus within 24 hours of infection without incidental damage to the host cells. They also showed greater effect at higher doses. Researchers have obtained similar results when testing the molecule in cells infected with SARS-CoV-2, the virus that causes COVID-19.

Further studies have shown that the molecule blocked the accumulation of the virus by binding to the first 800-character site of the viral genome. Most of this series of RNA does not encode the protein itself, but it promotes protein production.

Researchers are working on new ways to treat COVID-19 infections using molecules that bind to the three-dimensional folds of the viral genetic material.Credits: Martina Zafferani, Duke University

This area is folded to form multiple bulges and hairpin-like structures.Using a technique called computer modeling Nuclear magnetic resonance spectroscopy, Researchers have been able to analyze these 3D RNA structures and identify where the compounds are bound.

Researchers are trying to figure out exactly how these compounds block the growth of the virus after it binds to the genome.

When it comes to using RNA as a drug discovery target, Hargrove says the field is still in its infancy. Part of the reason is that the RNA structure is unstable. They bounce much more than the corresponding proteins, making it difficult to design molecules that can interact with them in certain ways.

“The binding pocket you’re looking for may not exist in most cases,” Hargrove said.

In addition, 85% of the RNA in infected cells does not belong to the virus, but to the human host ribosome (cell particles made up of RNA and proteins). “There is a sea of ​​competition,” Hargrove said.

But Hargrove has hope. The first small molecule drug that works by binding directly to non-ribosome RNA rather than protein was approved by the FDA last August to treat people with a catastrophic disease called spinal muscular atrophy. rice field. “So there are many challenges, but it’s not impossible,” Hargrove said.

Researchers are applying for patents on their method. They want to modify the compound to make it more potent and test it in mice to “see if this is a viable drug candidate,” Hargrove said.

Researchers say this isn’t the first time the coronavirus has caused an outbreak, and it’s likely not the last. In the last 20 years, the same virus family has been the cause of SARS. SARS occurred in China, spread to more than 20 countries in 2002, and MERS was first reported in Saudi Arabia in 2012.

The researchers found that the RNA loops and bulges they identified were essentially unchanged by evolution between related coronaviruses in bats, rats, and humans, including those that caused the development of SARS and MERS. I decided. This means that their method may be able to fight more than SARS-CoV-2, the virus that causes COVID-19.

Obviously, it will be a valuable weapon for more antivirals, so we will be better prepared when the next pandemic occurs. Having more medicine at hand has another advantage: fighting resistance. The virus mutates over time. When drugs with different mechanisms of action can be combined, virus According to Hargrove, resistance to all of them can develop at the same time, making treatment impossible.

“This is a new way to think about RNA virus antivirals,” says Hargrove.

A new drug candidate for hand-foot-and-mouth disease was found

For more information:
Martina Zafferani et al, Amilorides Inhibit SARS-CoV-2 Replication by Targeting RNA Structures, Science Advances (2021). DOI: 10.1126 / sciadv.abl6096..

Provided by
Duke University

Quote: COVID-19: Coronavirus entangled RNA strands were obtained from https: // 26, 2021 (November 2021) 26th) may offer new ways to treat. Tangled-strand-rna.html

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Coronavirus entangled RNA strands may offer new ways to treat infected people

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