Creating a new drug from scratch takes many years and billions of dollars. While discovery of new molecules against SARS-CoV-2 and other emerging viruses is imperative, the world also needs solutions for COVID-19 now. This is why there has been wide interest in repurposing existing drugs, for which safety and pharmacologic profiles are already available, as a viable strategy to save critical time and resources and quickly discover potential candidate drugs to combat the pandemic.
Dr. Paul Lieberman is a molecular virologist in Wistar’s Cancer Center, better known for his pioneering studies on how certain viruses persist in the body in a latent, long-term infection that can lead to cancer. He leads a talented drug-discovery team that has created first-in-class molecules directed against Epstein-Barr virus (EBV) as a novel therapeutic approach for potentially treating EBV-associated cancers including Burkitt’s lymphoma, nasopharyngeal carcinoma and Hodgkin’s lymphoma.
Applying their antiviral drug discovery expertise and innovative methods to "drug" the RNA component of viruses and cancer cells, the Lieberman lab is now working on a drug-repurposing project to quickly identify FDA-approved molecules that trap and inactivate SARS-CoV-2 RNA, the genetic material that carries the life information for the virus, just like DNA does in our cells.
SARS-CoV-2 RNA forms unique three-dimensional structures known as pseudoknots that are essential for viral replication and for the ability of the SARS-CoV-2 virus to cause disease. RNA pseudoknots may be a promising new target for therapeutic intervention.
Working closely with the Molecular Screening Facility, which provides state-of-the-art technologies and industry standard expertise, Dr. Lieberman and his team rapidly set up a high-throughput, novel screening assay based on identifying molecules that bind to the SARS-CoV-2 pseudoknot structures and disrupt their function. His team is in the process of evaluating thousands of FDA-approved small molecule drugs.
The lead candidates identified in the screen will then be further tested in cells and in preclinical models for their ability to stop infection and disease progression, and eventually to advance the best molecules into the clinic.
"We are taking a new, very focused approach to evaluate existing molecules," said Dr. Lieberman. "This allows us to look for a very specific activity to deploy against the virus in molecules that have already tested safe in humans."
Because RNA pseudoknot structures are similar in other coronaviruses, the outcome of this project could also have broader applications against other respiratory diseases.