COVID-19 Drugs: Cidofovir, Abacavir, Valganciclovir, Stavudine, And Entecavir Identified As Being Able To Shut Down SARS-Cov-2 Polymerase Reaction
: The SARS-CoV-2 coronavirus typically uses a protein called polymerase to replicate its genome inside infected human cells. Studies have shown that terminating the polymerase reaction will stop the growth of the coronavirus, leading to its eradication by the human host's immune system.
Now researchers from Columbia University and the University of Wisconsin-Madison have identified a library of molecules that shut down the SARS-CoV-2 polymerase reaction, a key step that establishes the potential of these molecules as lead compounds to be further modified for the development of COVID-19 therapeutics. Five of these molecules are already FDA-approved for use in the treatment of other viral infections including HIV/AIDS, cytomegalovirus, and hepatitis B.
The research findings were was published in the journal: Antiviral Research
The research team from Columbia University initially reasoned that the active triphosphate of the hepatitis C drug sofosbuvir and its derivative could act as a potential inhibitor of the SARS-CoV-2 polymerase based on the analysis of their molecular properties and the replication requirements of both the hepatitis C virus and coronaviruses.
The team led by Dr Jingyue Ju, Dr Samuel Ruben-Peter G. Viele Professor of Engineering, Professor of chemical engineering and pharmacology, and director of the Center for Genome Technology & Biomolecular Engineering at Columbia University, then collaborated with Dr Robert N. Kirchdoerfer, assistant Professor of biochemistry and an expert in the study of coronavirus polymerases at University of Wisconsin-Madison's Institute for Molecular Virology and the department of biochemistry.
In previous experiments testing the properties of the polymerase of the coronavirus that causes SARS, the researchers found that the triphosphate of sofosbuvir was able to terminate the virus polymerase reaction. They then demonstrated that sofosbuvir and four other nucleotide analogs (the active triphosphate forms of the HIV inhibitors Alovudine, Zidovudine, Tenofovir alafenamide, and Emtricitabine) also inhibited the SARS-CoV-2 polymerase with different levels of efficiency.
Utilizing the molecular insight gained in these investigations, the team devised a strategy to select 11 nucleotide analog molecules with a variety of structural and chemical features as potential inhibitors of the polymerases of SARS-CoV and SARS-CoV-2. While all 11 molecules tested displayed incorporation, six exhibited immediate termination of the polymerase reaction, two showed delayed termination, and three did not terminate the polymerase reaction.
Significantly prodrug medications of five of these nucleotide analogs (Cidofovir, Abacavir, Valganciclovir/Ganciclovir, Stavudine, and Entecavir) that terminate the SARS-CoV-2 polymerase reaction are FDA-approved for the treatment of other viral infections and their safety profiles are well established.
The researchers said that once the potency of the drugs to inhibit viral replication in cell culture is demonstrated in future investigations, then the candidate molecules an
d their modified forms may be evaluated for the development of potential COVID-19 therapies.
Dr Ju told Thailand Medical News, "In our efforts to help tackle this global emergency, we are very hopeful that the structural and chemical features of the molecules we identified, in correlation with their inhibitory activity to the SARS-CoV-2 polymerase, can be used as a guide to design and synthesize new compounds for the development of COVID-19 therapeutics. We are extremely grateful for the generous research support that enabled us to make rapid progress on this project. I am also grateful for the outstanding contributions made by each member of our collaborative research consortium."
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