Countries around the world are now rushing to vaccinate their populations against SARS-CoV-2, the virus that causes COVID-19. In the U.S., more than half of adults are now fully vaccinated. But new infections still occur daily. Better treatments are needed to reduce hospitalizations and deaths, and to help prevent spread of the virus.
The full genome of SARS-CoV-2 has been available to scientists since January 2020. Researchers have also used advanced microscopy techniques to map the 3D structure of the virus proteins in detail. Together, this information lets scientists search for new drugs to treat COVID-19 that are targeted specifically to its structure and functions.
In a new study, a research team led by Tracey Rouault, MD, from NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) looked for new ways to target an enzyme produced by SARS-CoV-2 called RNA-dependent RNA polymerase (RdRp).
SARS-CoV-2 needs RdRp to copy its genetic material once it’s gained entry into human cells. Shutting down RdRp could potentially stop viral replication and prevent disease progression. The results were published recently in Science.
Previous studies of the SARS-CoV-2 RdRp structure suggested that it requires zinc to do its job. However, clusters of iron and sulfur (Fe-S), which are less stable, can fill the same structural role. The team analyzed the sequence of RdRp to identify two potential sites for such Fe-S clusters. They then showed that iron and sulfur, not zinc, are needed at these sites for the protein to function optimally. When the researchers eliminated Fe-S clusters from RdRp, the ability of the enzyme to copy the virus’s genetic material was impaired.
Since Fe-S clusters are fragile, the researchers next tested whether they could be degraded by drugs. The team focused on a drug called TEMPOL, which can break up Fe-S clusters. TEMPOL has previously been tested for other uses in people and does not appear to have serious side effects.
The researchers found that TEMPOL inhibited RdRp when tested in human cells. Next, they infected cells with SARS-CoV-2 and administered TEMPOL. The drug blocked the virus from replicating. This inhibition was seen at doses that animal studies of TEMPOL in other diseases have shown could be achieved in tissues such as the lungs and salivary glands after oral administration.
“Given TEMPOL’s safety profile and the dosage considered therapeutic in our study, we are hopeful,” Rouault says. “However, clinical studies are needed to determine if the drug is effective in patients, particularly early in the disease course when the virus begins to replicate.”
The study team plans on conducting additional animal studies with TEMPOL. They are also seeking opportunities to evaluate it in a clinical study of COVID-19.
Source: Maio N, Lafont BAP, Sil D, Li Y, Bollinger JM Jr, Krebs C, Pierson TC, Linehan WM, Rouault TA. Fe-S cofactors in the SARS-CoV-2 RNA-dependent RNA polymerase are potential antiviral targets. Science. 2021 Jun 3:eabi5224.