Session Info
Accelerating the Development of Orally Bioavailable Therapeutics for Beta-Coronaviruses with Structure-based Molecular Design
Problem
There is a critical need for new antiviral drugs for treating infections of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). New drugs are crucial for rapid therapeutic response to COVID-19, supporting ongoing vaccination campaigns and expanding future antiviral drug options. SARS-CoV-2 variants can evade vaccines and antibody treatments; new variants continue to emerge and are expected to cause future outbreaks. The problem is relevant to national and global public health and is specifically important to economic stability and national security.
A team of ORNL scientists led by Brian Sanders has developed a potent and selective covalent inhibitor of the papain-like protease of SARS-CoV-2. Credit: Carlos Jones/ORNL, U.S. Dept. of Energy
Solution
Through rational and computational design, an ORNL team developed a potent and selective covalent inhibitor of the papain-like protease (PLpro) of SARS-CoV-2. PLpro is a critical target because it is essential for viral proliferation and dysregulates the host immune response. The team’s best lead to date has a half-maximal inhibitory concentration of 38 nM and half-maximal effective concentration in multiple SARS-CoV-2 variants ranging from 0.32–1.3 µM in vitro. However, in vivo efficacy is limited by rapid metabolic degradation. The team aims to improve the metabolic stability and oral bioavailability by designing new compounds based on our current best leads.
Impact
A successful therapeutic could capture a significant percentage of the total coronavirus current and future therapy market. Investments from domestic and international governments for preparedness stocks for future novel coronavirus outbreaks offer potential revenue. There has been a significant loss of life due to SARS-CoV-2 infections over the last three years, upwards of 6.8 million lives lost. Accordingly, there is a desperate need for new antiviral drugs that would have an enormous societal benefit on global health, security, and economics.
Publications
Sanders, B. C.; Pokhrel, S.; Labbe, A. D.; Mathews, I. I.; Cooper, C. J.; Davidson, R. B.; Phillips, G.; Weiss, K. L.; Zhang, Q.; O’Neill, H…. Parks, J.M. Potent and selective covalent inhibition of the papain-like protease from SARS-CoV-2. Nat. Commun. 2023, 14 (1), 1733.
Intellectual Property
Invention Ref. No. 202004743. US Patent Applic. No. 17/896,182 entitled “Covalent Inhibitors of Coronavirus Papain-Like Protease” filed on August 26, 2022; PCT Patent Applic. No. US2022/041629 filed on August 26, 2022.
Contact
For more information, please contact Jennifer Caldwell (865-574-4180, caldwelljt@ornl.gov).
