Antiviral Drugs and COVID-19
SARS-CoV-2 (COVID-19) multidrug high-throughput screening (collaboration with Harvard University and the University of California)
COVID-19 is a devastating respiratory and inflammatory illness caused by a new coronavirus that is rapidly spreading throughout the global population. SARS-CoV-2 is the virus that causes COVID-19. A debilitating disease socially, economically and biologically, COVID-19 became a pandemic in 2020. Research in the Drug Discovery, Design and Optimization for Novel Therapeutics Lab is designed to attack the virus at crucial progression stages. First, we aim to block the virus from binding to the cell. Second, we endeavor to block the virus from gaining entry into the cell. And third, we seek to block the virus from replication within any infected cells through using a combination of drugs targeting all three of those stages, simultaneously.
The threefold goal is to:
- Prevent binding of virus to its cell surface receptor
- Block membrane fusion of the virus via the endosomal pathway
- Stop viral replication by preventing the main protease (Mpro) from generating the proteins needed to assemble additional viral particles
The lab has developed a cooperative platform for cellular, molecular and computational techniques to provide groundbreaking new insights into COVID-19 druggability and improve our drug discovery efforts against SARS-CoV-2.
Using a polypharmaceutical approach for COVID-19 has been used previously with good success in other diseases such as HIV, and we hope to find synergetic (additively protective) agents that prevent the virus from gaining access to human hosts. Although vaccines now exist, these prophylactic agents may find use with immunocompromised individuals and in other scenarios.
The lab will be targeting SARS-CoV-2 proteins by generating new libraries of compounds to block SARS-CoV-2 at three important stages in the virus progression:
- Binding. Spike protein S2 and angiotensin-converting enzyme 2 (ACE2) — host receptor protein (human)
- Entry. Transmembrane serine protease 2 (TMPRSS2) plus alternatives that include protease cathepsins — host enzyme protein (human)
- Replication. Mpro — viral enzyme
Additional targets are under consideration as well.
We have preliminary data from screening over 30 million compounds, which also includes more than 3,000 known clinical trial drugs, resulting in a compound library of approximately 1,000 to be screened against live virus with our collaborators at University of California in their Biosafety Level 3 (BSL-3) facility.
Furthermore, the lab's drug-screening platform, complemented by fragment-based drug discovery (FBDD), pharmacophore modeling using 3D quantitative structure-activity relationship (3D-QSAR) and X-ray cocrystallized targets, provide much needed data for structure-activity relationships to optimize our hits into low nanomolar biochemical toolkit compounds for further screening. The lab's team then performs safety profiling in human cell lines (lung and heart) using data derived from the live virus screening and organ-on-a-chip output in cooperation with Y. Shrike Zhang, Ph.D. After several iterations and complete preclinical screening for safety and efficacy, the top compounds will be selected to move forward as the lead candidates. In vitro assays include human ether-a-go-go-related gene (hERG) assays for off-target effects in heart, microsomal liver assays (metabolic effects), and Ames assays (chemical is mutagenicity) and in vivo assays will be conducted using human ACE-transgenic mice.
Dr. Caulfield's team has been actively working on COVID-19 and utilizing a structure-function based drug design and high-throughput screening of small molecules.
- Coban MA, Morrison J, Maharjan S, Hernandez Medina DH, Li W, Zhang YS, Freeman WD, Radisky ES, Le Roch KG, Weisend CM, Ebihara H, Caulfield TR. Attacking COVID-19 progression using multi-drug therapy for synergetic target engagement. Biomolecules. 2021; doi.org/10.3390/biom11060787.
- Onweni CL, Zhang YS, Caulfield T, Hopkins CE, Fairweather L, Freeman WD. ACEI/ARB therapy in COVID-19: The double-edged sword of ACE2 and SARS-CoV-2 viral docking. Critical Care. 2020; doi:10.1186/s13054-020-03195-9.
- Ramakrishna JM, Libertin CR, Siegel J, Binnicker MJ, Harris D, Matcha GV, Caulfield T, Freeman WD. Three-tier stratification for CNS COVID-19 to help decide which patients should undergo lumbar puncture with CSF analysis: A case report and literature review. Romanian Journal of Internal Medicine. 2020; doi:10.2478/rjim-2020-0031.