First-Ever Molecules that Target SARS-CoV-2 RNA and Prevent Replication Could Cure COVID-19

Researchers are working on new ways to cure COVID-19 infections, such as using molecules that bind to folds in the SARS-CoV-2 virus’s RNA genome.

Researchers at Duke University (Durham, N.C., USA) believe that the complex shapes that RNA takes on as it folds upon itself could have untapped therapeutic potential in the fight against COVID-19. The team has identified chemical compounds that can latch onto these 3D structures and block the virus’s ability to replicate.

To infect human cells, the coronavirus must break in, deliver its genetic instructions in the form of RNA, and hijack the body’s molecular machinery to build new copies of itself. The infected cell becomes a virus factory, reading the 30,000 nucleotide “letters” of the virus’s genetic code and churning out the proteins the virus needs to replicate and spread. Most antivirals - including remdesivir, molnupiravir and Paxlovid, the only antiviral drugs for COVID-19 that have been FDA-approved or are in line for approval - work by binding to these proteins.

However, the Duke University researchers are taking a different approach. They have identified the first molecules that take aim at 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 the RNA strand folds into. When they tested the molecules on monkey cells infected with SARS-CoV-2, the virus that causes COVID-19, they found that the compounds reduced the amount of virus within 24 hours of infection without causing collateral damage to their host cells. They also showed greater effects at higher doses.

Further work showed that the molecules stopped the virus from building up by binding to a site in the first 800 letters of the viral genome. Most of this stretch of RNA doesn’t code for proteins itself but drives their production. The region folds in on itself to form multiple bulges and hairpin-like structures. Using computer modeling and a technique called nuclear magnetic resonance spectroscopy, the researchers were able to analyze these 3D RNA structures and pinpoint where the chemical compounds were binding. The researchers are still trying to figure out exactly how these compounds stop the virus from multiplying, once they’re bound to its genome.

The researchers have a patent pending on their 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 determined that the loops and bulges of RNA they identified have remained essentially unchanged by evolution across related coronaviruses in bats, rats and humans, including the ones that caused the SARS and MERS outbreaks. That means their method might be able to fight more than just SARS-CoV-2. Clearly, more antivirals would be valuable weapons to have, so when the next pandemic hits we’ll be better prepared. Having more drugs on hand would have another benefit: fighting resistance. Viruses mutate over time. Being able to combine drugs with different mechanisms of action would make it less likely that the virus could develop resistance to all of them simultaneously and become impossible to treat.

“These are the first molecules with antiviral activity that target the virus’s RNA specifically, so it's a totally new mechanism in that sense,” said Amanda Hargrove, a chemistry professor at Duke University. “This is a new way to think about antivirals for RNA viruses.”

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