Next-Gen Antiviral Agents Block Function Of Untranslated RNA
By Deborah Borfitz
May 26, 2021 | As COVID-19 has so painfully revealed, therapeutic agents are needed to hold diseases at bay until bespoke vaccines can be developed. Even with the breakneck speed at which vaccines have become available during the current pandemic, millions of people perished during the yearlong wait.
Interest in viruses in general has intensified, as has the realization that they are as important to proactively confront as bacterial superbugs, says Mike Hannon, a chemistry professor at the University of Birmingham (U.K.). As with overcoming antibiotic resistance, outwitting a virus with pandemic potential will require a “suite” of approaches in the therapeutic arsenal.
One promising new way of stopping a viral pathogen from replicating is with drugs attacking the genetic information on the virus itself—its RNA. Efforts up to now have focused on targeting a virus’s proteins, says Hannon, but he and his colleagues have identified cylindrically shaped molecules that can block the function of untranslated RNA.
Forming the front and back sections of the viral genome, untranslated RNA is not fully understood by scientists other than its apparent helper role in regulating replication and gene expression of the virus, Hannon explains. That seemingly makes it an ideal target for next-generation anti-viral drugs.
The university-based research team has long been interested in unusual nucleic acid structures and was originally focused on DNA. Actual DNA, Hannon points out, often bears little resemblance to textbook illustrations depicting only its main double helix structure resembling a twisted ladder.
RNA can also have helical structures, but other, less picturesque structural elements are the bulges and Y-shaped junctions of untranslated RNA, which is “absolutely crucial” to viral function. These features create small holes that the novel cylindrical molecules can readily slip into and take up residence to halt the replication process, he says, as detailed in a study newly published in Angewandte Chemie (DOI: 10.1002/anie.202104179).
As researchers have just demonstrated, the approach could be effective against the SARS-CoV-2 virus. While the research may not be useful for the COVID-19 pandemic now that vaccines have hit the market, says Hannon, the compound could well serve as a broad spectrum anti-viral drug. Earlier modeling and in vitro analysis by the team showed its utility against the HIV virus.
In President Biden’s National Strategy for the COVID-19 Response and Disaster Preparedness, issued in January, he notes, one of the listed goals is to “Develop broad-spectrum antivirals and prioritize other viral classes that present emerging threats to prevent future viral pandemics.” It calls for federal promotion of discovery and development of antivirals with broad-spectrum activity against coronaviruses and, later, other viral classes that represent emerging pandemic threats.
Ideal Size And Shape
The discovery of the new anti-viral target was a culmination of efforts by a “melting pot” of colleagues in the biosciences and computer sciences departments at the University of Birmingham as well as its medical school, says Hannon. These included fruitful experiments looking at the way the cylindrical compounds bind to RNA, molecular dynamic simulations to model the interactions, and tests of the compound demonstrating its ability to stop viral replication in cells infected with the SARS-CoV-2 virus.
The star of the show are molecules of nanometer dimensions—2 x 1 nanometers, to be exact—in a shape resembling a twisted version of a chocolate bar (Toblerone) popular in the U.K., Hannon says. This is a bit bigger than small molecule drugs whose structure typically consists of a few interconnected rings.
As it turns out, the Toblerone-looking molecules are “just the right size and shape” to get into the little cavities that form on untranslated RNA, he adds. Their positive charge makes them strongly attracted to RNA, but they especially like to go into holes by “sliding down the RNA bases... it’s very beautiful in fact.”
Scientists have been working with the supramolecular cylinders since the turn of the century, but their potential as an anti-viral agent was only discovered a couple years ago, says Hannon. “It’s a fascinating species, unlike anything that has been studied before.”
Research on their effectiveness as a treatment against potentially lethal viruses such as SARS-CoV-2 is made possible by state-of-the-art containment level 3 facilities at the University of Birmingham, he says. Such facilities require rigorous training and protective gear and are concentrated at a handful of universities and research institutes.
Next steps are to gain a fuller picture of the mechanism of action of the nano-sized agents, which to date have been tested only in simple cell lines, Hannon says. The research team is interested in learning how different types of tissues might respond to the agent, or if there are any issues they need to molecularly engineer in or around—or if an even better molecule can be produced.
In addition to stopping viruses from replicating, the novel molecules could potentially be carried to DNA targets to stop cancer cells from replicating, he says. Unlike chemistry-based cancer agents on the market, “they don’t seem to cause permanent damage to cells,” although studies in humans have yet to be conducted.
For the foreseeable future, the utility of the molecules in treating viral infections is likely to be the focus of attention, he adds. Before clinical trials can even be discussed, researchers will need to identify appropriate models for preclinical testing—one of the perennial challenges in virology, since the response of animals and humans to viral infection can be vastly different.
