Targeted therapeutics for COVID-19
Siddappa N. Byrareddy, PhD
Professor & Vice Chair of Research
Dept of Pharmacology & Experimental Neuroscience
University of Nebraska Medical Center
Since the discovery of SARS-CoV-2, more than 225 million people have been infected to date, and 4.6 million people have succumbed to death worldwide. Significant efforts were made to develop an emergency vaccine and make it available to all adults. However, children, pregnant women, and immunosuppressed people are still at risk of acquiring and suffering from diseases. Therefore, alternative strategies are needed to block/inhibit viral entry to host cells. Herein, we identified two lead compounds; one blocks the attachment of spike with ACE2, while the other is a PI3K-α-m-TOR/(BRD2/BRD4) inhibitor that blocks two orthogonal pathways necessary for SARS-CoV-2 pathogenesis in human cells. Using a computer-aided drug design approach, we first performed a virtual screening of a library of drug-like compounds that had the potential to bind at the ACE2/Spike interface to identify the SARS-CoV-2 entry inhibitors. We identified several lead compounds and tested them in vitro for antiviral and biophysical activities. Recently, a proteomic analysis study identified several host cellular targets essential for SARS-CoV-2 pathogenesis. A small-molecule SF2523 was identified, which inhibits two of the critical targets, the bromodomain and extra-terminal domain proteins (BETs: BRD2/BRD4) and mTOR: at nanomolar potency. We have measured inhibitory effects, synergy, and molecular modeling for both antiviral and cellular targets in biologically relevant human epithelial cells using wild type and variants of SARS-COV-2. I will discuss in detail of discovery and evaluation of various targeted approaches currently ongoing in our laboratory.
Thursday, September 30, 2021 at 12:00 PM
2251 Veterinary Medicine Basic Sciences Building
2001 South Lincoln Avenue, Urbana
For more information contact the Department of Pathobiology at 217-333-2449, email klp68@illinois.edu.
