The proteases of SARS-CoV-2 are scissor-like enzymes that precisely cut longer viral protein precursors into functional units required for pathogenesis.
Project 3 of the Midwest AviDD Center is developing chemical inhibitors of the main SARS-CoV-2 protease, Mpro, which is required for 11 distinct cutting events that are all required for virus replication. This enzyme is therefore an excellent drug target as demonstrated by the clinical protease inhibitor, Paxlovid (Pfizer), and other potent drugs developed for other viral proteases including those of HIV-1 and HCV.
However, additional Mpro inhibitors are required to combat the inevitable problem of viral variants that become resistant to drug treatment. Several such variants already exist in the human population, and, over time, these rare isolates may become more frequent and undermine the efficacy of Paxlovid and other drugs in development.
The Project 3 team is therefore using a combination of traditional and innovative screening strategies to identify and validate new Mpro inhibitors. Top candidates are then developed further in close collaboration with chemistry, structural biology, and virology teams. In addition to many training opportunities, the major deliverable from this work will be new inhibitors of this essential viral enzyme that can be collaboratively developed into next-generation drugs.
Project 3 is also utilizing similar approaches to target the essential protease of Zika virus, which is another virus with pandemic potential.