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The battle to suppress, treat, or eradicate the novel SARS-CoV-2 virus and its emerging variants that cause COVID-19 disease is ongoing and will likely be as such for the foreseeable future. Multiple, highly efficacious mRNA vaccinations have been developed that can protect individuals from contracting the disease or dramatically blunt its effects. More recently, novel antiviral agents have been developed by several pharmaceutical companies and begun clinical safety and efficacy trials. On November 4, Merck & Co Inc’s antiviral drug molnupiravir became the first such agent to gain regulatory approval when it was authorized for use by the United Kingdom’s Medicines and Healthcare Products Regulatory Agency. While the research and development of novel agents continues, so does research to examine existing, approved compounds that may be leveraged to fight the virus.
Research from a multidisciplinary UPMC and University of Pittsburgh team, including faculty from the Division of Pulmonary, Allergy, and Critical Care Medicine, the Acute Lung Injury Center, the Vascular Medicine Institute, and the Division of Cardiology, has found two potential U.S. Food and Drug Administration (FDA)-approved compounds which appear in preliminary studies to have the ability to interfere with molecular proteomic processes necessary for the virus to infiltrate healthy cells and replicate.
Bill B. Chen, PhD, was the senior author of the study. Dr. Chen is a professor of medicine in the Division of Pulmonary, Allergy and Critical Care Medicine, director of the Small Molecule Therapeutic Center, and co-director of the Acute Lung Injury Center of Excellence.
Dr. Chen's team's research focused on compounds that could inhibit or otherwise degrade the transmembrane serine protease 2 (TMPRSS2) cell surface protein, which is crucial for the SARS-CoV-2 virus's ability to infiltrate epithelial lung cells (and others) and propagate. Previous research on coronaviruses has shown the importance of TMPRSS2 to the process of viral infection, working to activate the spike protein seen in the SARS-CoV-2 virus.
Dr. Chen's team analyzed more than 2,500 small molecules that are either FDA-approved or currently being examined in clinical trials in an attempt to find ones that could interfere with TMPRSS2 and potentially block the virus's ability to infiltrate healthy cells.
Finding and potentially using existing FDA-approved agents could significantly speed the ability to conduct clinical trials in human subjects.
Of the agents analyzed, two show significant promise any may warrant further research or clinical trials. The first is homoharringtonine, an agent used in the treatment of chronic myeloid leukemia. The second agent is halofuginone, a drug currently involved in clinical trials for treating scleroderma. While additional trials and testing are required, it is possible based on the preliminary findings that these agents may be able to be used alone, or in combination, and in combination with other agents already in use, such as monoclonal antibody therapy and the antiviral remdesivir, to better combat the virus and its evolving mutations.
Because mutations in the coronavirus’s spike protein can render previously effective blockades useless (e.g., vaccines, monoclonal antibody therapy), targeting alternate pathways or molecular processes that are crucial to the success of the virus, yet not part of the mutagenic process and remain stable are crucial to continuing the fight against the novel virus.
Chen Y, Lear TB, Evankovich JW, Larsen MB, Lin B, Alfaras I, Kennerdell JR, Salminen L, Camarco DP, Lockwood KC, Tuncer F, Liu J, Myerburg MM, McDyer JF, Liu Y, Finkel T, Chen BB. A High-Throughput Screen for TMPRSS2 Expression Identifies FDA-Approved Compounds That can Limit SARS-CoV-2 Entry. Nat Commun. 2021; 12:3907. Epub ahead of print.