Molecules Shut Down SARS-Cov-2
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Molecules that shut down SARS-Cov-2 polymerase reaction

The coronavirus – SARS-CoV-2 causing the COVID-19 pandemic around the world, uses a protein called polymerase to replicate its genome inside infected human cells. Stopping the polymerase reaction will certainly terminate the development of the coronavirus, leading to its obliteration by the immune system in humans.

A library of molecules that shut down the SARS-CoV-2 polymerase reaction, an essential step that develops the potential of these molecules as lead substances to be further modified for the development of therapies against coronaviruses has been identified by the scientists at Columbia Engineering and the University of Wisconsin-Madison. 5 of these molecules are already approved for use in the therapy of other viral infections comprising hepatitis B, HIV/AIDS, and cytomegalovirus by the Food and Drug Administration. The outcomes of the study are published in the journal Antiviral Research.

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Molecules Shut Down SARS-Cov-2
The incorporation of three nucleotide analogs Carbovir-5′-Triphosphate (Car-TP), Entecavir-5′-Triphosphate (Ent-TP), and Ganciclovir-5′-Triphosphate (Gan-TP) by SARS-CoV-2 polymerase terminates the viral polymerase reaction. The reaction products were detected by MALDI-TOF mass spectrometry. Image Credit: Jingyue Ju,/Columbia Engineering

Based upon the analysis of hepatitis C drug sofosbuvir and its by-product’s molecular properties and the replication demands of both the coronaviruses and hepatitis C virus, the team initially reasoned that the active triphosphate of the hepatitis C drug sofosbuvir and its by-product can act as a potential inhibitor of the SARS-CoV-2 polymerase. Jingyue Ju, Samuel Ruben-Peter G Viele Professor of Engineering, Director of the Center for Genome Technology & Biomolecular Engineering, Columbia University, and Professor of chemical engineering and pharmacology was the lead scientists of this research. They then teamed up with Robert N Kirchdoerfer, Assistant professor of biochemistry and a professional in the research of coronavirus polymerases, Department of biochemistry, Institute for Molecular Virology, the University of Wisconsin-Madison.

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The scientists discovered that the triphosphate of sofosbuvir was able to terminate the virus polymerase reaction, in the previous set of experiments testing the properties of the polymerase of the coronavirus that causes SARS. The scientists further showed that the SARS-CoV-2 polymerase was inhibited bt sofosbuvir as well as 4 other nucleotide analogs (the active triphosphate forms of the HIV inhibitors Zidovudine, Emtricitabine, Tenofovir alafenamide, and Alovudine) – with various levels of efficiency.

An approach to select 11 nucleotide analog molecules as potential inhibitors of the polymerases of SARS-CoV and SARS-CoV-2 with a variety of structural as well as chemical features was devised by the team utilizing the molecular understanding gained in these analyses. The molecules analyzed showed that – 11 molecules showed incorporation, 6 showed immediate termination of the polymerase reaction, 2 showed delayed termination, and polymerase reaction did not stop with 3 of the molecules.

Prodrug medicines of 5 of nucleotide analogs, including Abacavir, Cidofovir, Entecavir, Valganciclovir/Ganciclovir, and Stavudine that terminate the SARS-CoV-2 polymerase reaction have well-developed safety profiles and are FDA-approved for the treatment of other viral infections. The candidate molecules and their altered forms may be assessed for the development of prospective treatments against COVID-19 as soon as the potency of the medicines to inhibit viral replication in cell culture is demonstrated in future investigations.

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We are really optimistic that the chemical, as well as structural features of the molecules we identified that inhibits the activity of SARS-CoV-2 polymerase, can be used as a guide to design and manufacture new substances to combat this COVID-19 pandemic, said Jingyue Ju.

He also added, we are exceptionally grateful for the generous research support that enabled us to make quick development on this research, and I am very thankful for the eminent contributions made by each person involved in our joint research consortium.

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Author: Sruthi S