New Drug Development against the Novel Coronavirus Rna Polymerase

Presently, there is a worldwide struggle with the novel coronavirus 2 (SARS-CoV2). Hence, there is an urgent need for identification of viral inhibitors that can overcome the limitations of current supportive therapies and thereby reduce the pressure on the health care system. Current research indicates that remdesivir (GS-5734), a precursor of a nucleotide analog, can effectively inhibit replication of the SARS-CoV2 ribonucleic acid (RNA). Two small and structurally distinct compounds—HP114 and HP446—that can inhibit the activity of influenza virus and enterovirus RNA polymerases, and are expected to inhibit SARS-CoV2, have recently been discovered at our laboratory through an in-house antiviral cell-based screening platform. Our preliminary results of the anti-SARS-CoV2 activity of HP114 and HP446 with African green monkey kidney epithelial cells (Vero-E6) in the Biosafety Level 3 Laboratory (BSL3) showed that the EC50 values of the candidate drugs HP114 and HP446, were less than 0.0625 μM and 0.3125 μM, respectively, which are in the same effective concentration range as the EC50 value of remdesivir (0.077 μM) in the same cells. Drug addition time-course experiments showed that HP114 inhibited every tested stage of the viral life cycle. The synthesis of viral RNA, viral proteins, and cytokine were inhibited by HP114 by using real-time polymerase chain reaction and western blotting. In future experimental design of this one-year project, our laboratory will: (1) perform in vitro experiments to determine whether the candidate drugs can inhibit the RNA polymerase activity of the virus (RdRp assay); and (2) combine the candidate drugs and remdesivir. Since HP114 and HP446 are not analogous to remdesivir, we expect that the combination of these candidate drugs and remdesivir will have enhanced antiviral effects, alleviating side effects and reducing viral resistance, thus improving the efficacy of remdesivir.

Project ID:PC10908-0081
External Project ID:MOST109-2327-B182-003