Researchers at Case Western Reserve University, Duke, and Rutgers lead work to understand how the novel coronavirus’s tangled RNA could help treat infected people
Scientists at Case Western Reserve, Duke, and Rutgers universities coronavirus genome have identified compounds within the coronavirus genome that have the potential to block its ability to replicate.
Their findings appeared Friday, Nov. 26, in the journal Science Advances.
“We reasoned that the unique shape of the virus’s RNA genome presented an opportunity to target it with small molecules that might hold potential to slow the virus’s ability to spread,” said Blanton S. Tolbert, the Rudolph and Susan Rense Professor of Chemistry at Case Western Reserve, one of the researchers leading the project. “And the early results are encouraging.”
Amanda Hargrove, a chemistry professor at Duke University, said in a news release that the work offered an untapped therapeutic potential to fight COVID-19: “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,” she said.
Tolbert and Hargrove are joined in the work by molecular biologist and virologist Gary Brewer and molecular biologist Mei-Ling Li, both of Rutgers. Other collaborators included researchers from the Washington University School of Medicine in St. Louis, the University of Nebraska-Lincoln, the University of Michigan, and the University of Glasgow..
The researchers also noted that the discovery could lead to treatments for other future viruses. They determined that the loops and bulges of RNA that they identified have remained essentially unchanged by evolution across related coronaviruses in bats, rats and humans, including those that caused the SARS and MERS outbreaks.
Tolbert said the collaboration began in February 2020 at an informal meeting among the three main research groups from CWRU, Duke and Rutgers at Duke University. “We laid out the first steps to inhibit SARS-CoV-2,” he said, “because the group anticipated that the virus might become a bigger public health concern than it was initially perceived.”
Other Case Western Reserve researchers involved were all from Tolbert’s lab: post-doctoral student Le Luo; and graduate students Christina Haddad, Jesse Davila-Calderon and Liang Yuan-Chiu, who has since graduated.
A better antiviral?
To infect cells, the coronavirus must break in, deliver its genetic instructions in the form of RNA, and hijack that cell’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 needed for the virus to replicate and spread.
Most antivirals-including remdesivir and molnupiravir, the only antiviral drugs that the U.S. Food and Drug Administration has approved or is considering for approval to protect against COVID-19 work by binding to these proteins.
But Tolbert, Hargrove and their team have taken a different approach. They’ve identified the first molecules that can take aim at the folds of RNA strands found in the complex 3D structure of the viral genome itself.
Building on early research
This new work builds on research first conducted by Hargrove, Tolbert and others in 2020, just as the COVID-19 pandemic started to make headlines.
That team was already investigating potential drug candidates to fight another RNA virus-Enterovirus 71, a common cause of hand, foot and mouth disease in children.
The group had identified a class of small molecules called amilorides that can bind to hairpin-like folds in the virus’s genetic material and disrupt its replication.
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 have a patent pending on their method and intend to modify the compounds to make them more potent, and then conduct animal testing “to see if this could be a viable drug candidate,” Hargrove said.