Targeting Programmed -1 Ribosomal Frameshifting in COVID-19 with Jonathan Dinman of UMD

Dr. Jonathan Dinman is a professor and the chair of the Department of Cell Biology and Molecular Genetics at the University of Maryland. He is also a member of the Program in Oncology at the University of Maryland Marlene and Stewart Greenebaum Cancer Center.
COVID-19 is caused by a member of the Coronavirus family called SARS-CoV-2. This virus is thought to have emerged into the human population from a wild source, most likely bats, in Wuhan China in late 2019. Hence the name, COronaVirus Infectious Disease-(20)19. As of September 1, 2020, the World Health Organization has documented over 25 million cases and over 850,000 deaths. Coronaviruses have relatively large genomes for viruses, composed of a single strand of RNA approximately 30,000 nucleotides in length. These genomes encode a developmental "program" that can be generally divided into three stages: 1) Host cell takeover; 2) viral RNA synthesis; and 3) new virus production. They use a molecular mechanism called Programmed -1 Ribosomal Frameshifting (-1 PRF) to switch from Stage 1 to Stage 2 of this program. Prior studies with other viruses, including the closely related SARS-CoV, demonstrated that interfering with this switch inhibits viral replication. Here, we use molecular genetics and biophysical methods to characterize the SARS-CoV-2 -1 PRF signal, and find that it is nearly identical to that of SARS-CoV. We demonstrate that a drug that inhibits SARS-CoV -1 PRF also inhibits that of SARS-CoV-2 and preliminary data indicate that it inhibits virus production in cell culture, and preliminary small molecule screens have identified new candidate drugs that target -1 PRF. Our current research is focused on characterizing SARS-CoV-2 frameshifting using a complementary suite of biophysical, molecular genetics, and virological approaches.