Drug Repurposing for Antiviral Therapies: Research and Strategies with High Throughput Screening
As the effects of the novel virus are felt worldwide, researchers across the globe are mobilizing to find anti-viral therapies to fight against this new infection. Tackling this challenge by traditional de novo drug discovery approaches is a critical piece of the puzzle but also demands time and sizable investments.
As an alternative approach, screening existing compounds that have been clinically studied and approved to treat other conditions or diseases also provides an important avenue to fight the pandemic. Plus, drug repurposing, if proven effective, has the potential for rapid clinical impact. These compounds have well-characterized pharmacokinetic, dosage, and safety data which could potentially be translated toward launching a clinical trial.
Current efforts are underway to deconvolute the outcomes of patients treated with clinically approved drugs. Dr. David Fajgenbaum, a physician responsible for repurposing an approved drug to treat his own rare disease, is generating a sophisticated repository for repurposed drugs used to treat patients infected by the new viral disease.
The CORONA Database
Dr. Fajgenbaum and his team, in conjugation with the Food and Drug Administration (FDA), have developed a database called CORONA – Covid Registry of Off-label & New Agents – to systemically parse data from over 9,000 patients infected by the novel virus. One notable feature of the viral infection is called the cytokine storm, in which the body’s own immune response begins to attack healthy, uncompromised cells. This reaction is shared between patients in our current pandemic situation and Dr. Fajgenbaum’s own rare disease called Castleman’s Disease.
Using the same methodology he used to treat his own disease, Dr. Fajgenbaum hopes approved drugs that can subside the effects of cytokine storm can be elucidated from the CORONA database and provide actionable treatments for doctors to treat patients. Being able to test and analyze compounds quickly and effectively will play a key role in helping to determine which compounds, and in turn which existing therapeutics, might be appropriate for a clinical trial. This effort requires innovative instruments and software.
For example, in a recent study, researchers at the Fraunhofer Institute for Molecular Biology and Applied Ecology IME in Hamburg, Germany curated a screening library of over 5,000 compounds. This library was then used in a high throughput screen against a Caco-2 cell line infected with the novel virus isolate in search of compounds that reduce viral induced cytotoxicity.
The final set of active hits contained over 50 compounds and has illuminated pathways sensitive to the novel virus lethality such as kinase signaling, p53 activation, and phosphodiesterase (PDE) pathways.
Instruments for Insights
To carry out this screen, researchers measured viral-induced cytotoxicity using the PerkinElmer Operetta® CLS™ high-content analysis system and Columbus™ software, determining multiple parameters such as morphology and cell confluency. The Operetta CLS System and Columbus software provide a powerful imaging and analysis platform that produces high resolution images and data for impactful physiological findings.
To confirm active compounds, orthogonal testing was carried out to screen Caco-2 cells by a luminescent ATP assay that measures cytotoxicity. This testing was conducted in 384-well plates on PerkinElmer’s EnVision® multimode plate reader.The EnVision multimode plate reader offers exceptional sensitivity and throughput in a variety of detection modalities including luminescence, HTRF®, and Alpha technologies.
Gaining actionable insights from this type of research and data can not only help identify potentially effective drug repurposing candidates for antiviral therapies, but also assist in investigating the viral disease mechanism of action which will expedite finding novel drugs to treat patients in our current pandemic. Using all the tools in the arsenal including this data and powerful life science instrumentation and software can accelerate the research which could in turn help save lives around the world.