An international research consortium has identified potential drug targets and therapies for the three coronaviruses—SARS-CoV-1, SARS-CoV-2, and MERS-CoV—that have caused recent epidemics and the current pandemic.
The team, which included representatives from EMBL’s European Bioinformatics Institute near Cambridge, several other academic teams from around the world, and two biotech companies, hopes that looking at all three viruses will not only help combat the current COVID-19 pandemic, but also to target new coronaviruses that arise in the future.
“These analyses demonstrate how biological and molecular information are translated into real-world implications for the treatment of COVID-19 and other viral diseases,” says Pedro Beltrao, Ph.D., a group leader at the European Bioinformatics Institute and senior researcher on this study.
“After more than a century of relatively harmless coronaviruses, in the last 20 years we’ve had three coronaviruses that have been deadly. By looking across the species, we have the capability to predict pan-coronavirus therapeutics that may be effective in treating the current pandemic, which we believe will also offer promising therapeutics for a future coronavirus as well.”
As reported in the journal Science, the researchers generated maps of all three viruses showing how viral and human proteins interact to search for potential targets for treatments.
They also tagged viral proteins as well as antibodies targeting certain SARS-CoV-2 proteins and observed how they reacted on a subcellular level, as well as investigating these interactions on a genetic level using RNAi and CRISPR technology.
This in-depth look revealed a number of host factors that impact infection with the SARS-CoV-2 virus. For example, a mitochondria-associated protein called Tom70 that interacts with both SARS-CoV-1 and SARS-CoV-2 may help promote infection and could therefore be a good drug target for treating infection with both these viruses.
The researchers also analyzed a large data set of 738,933 patients in the U.S. with a recorded SARS-CoV-2 infection to assess whether drugs licensed for other indications could have a beneficial effect against COVID-19 infection.
They observed some interesting outcomes. For example, people taking the non-steroidal anti-inflammatory pain killer indomethacin were less likely to be admitted to hospital with COVID-19 than those taking the painkiller celecoxib. Indomethacin inhibits prostaglandin E synthase type 2, a protein that helps SARS-CoV-2 infection progress.
Similarly, psychiatric patients prescribed sigma-ligand typical antipsychotics in the cohort appeared to have a better outcome from COVID-19 than those given atypical antipsychotics that do not bind to the sigma-1 target.
In a final part of the study, the researchers assessed whether their data could help predict new targets for COVID-19 drugs.
Combining an analysis of genome wide association studies from the COVID-19 Host Genetics Initiative with their protein mapping information led to the finding that high levels of soluble interleukin-17 receptor A are linked with lower COVID-19 risk. This protein binds to the virus, resulting in decreased infection levels due to genetic disruption, suggesting this pathway could be relevant for designing new therapies to target SARS-CoV-2 and perhaps other coronaviruses.
“Replication in other patient cohorts and further work will be needed to see if there is therapeutic value in these connections,” write the authors, “but at the very least we have demonstrated a strategy wherein protein network analyses can be used to make testable predictions from real-world, clinical information.”
