POLYMERASE, a protein used by the SARS-CoV-2 virus to replicate its genome while inside infected human cells, is a target that researchers from Columbia University, New York City, New York, USA, and University of Wisconsin-Madison, Madison, Wisconsin, USA, have been investigating for its potential in the elimination of the virus. It is thought that by terminating this polymerase, the virus will stop replicating and the human host’s immune system can eradicate the virus.
The researchers have identified a library of molecules that have the capability of shutting down the SARS-CoV-2 polymerase reaction, a key step in the research and development pipeline of COVID-19 therapeutics. Of the identified compounds, five were U.S. Food and Drug Administration (FDA)-approved antivirals for other viral infections. In an earlier set of experiments, the researchers tested the polymerase of SARS-CoV and found that the viral polymerase reaction could be terminated by the triphosphate of sofobuvir, a hepatitis C drug. In total, 11 molecules, which are currently used for viral infections such as HIV, hepatitis B, and cytomegalovirus, were tested against SARS-CoV-2, all of which displayed delayed incorporation. Of note, six exhibited immediate termination of the polymerase reaction, including carbovir, ganciclovir, stavudine, and entecavir; two showed delayed termination; and three did not terminate the polymerase reaction.
Study leader Prof Jingyue Ju, Columbia University, commented: “In our efforts to help tackle this global emergency, we are very hopeful that the structural and chemical features of the molecules we identified, in correlation with their inhibitory activity to the SARS-CoV-2 polymerase, can be used as a guide to design and synthesise new compounds for the development of COVID-19 therapeutics.” Because of the already established safety profiles of the prodrug medications for five of these molecules (cidofovir, abacavir, valganciclovir/ganciclovir, stavudine, and entecavir), it is hoped that these will be lead compounds for COVID-19.