Researchers identify multiple molecules that shut down SARS-Cov-
2 polymerase reaction

Date:
June 30, 2020
Source:
Columbia University School of Engineering and Applied Science
Summary:
Researchers 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.



FULL STORY ========================================================================== [Coronavirus illustration | Credit: (c) dermatzke / stock.adobe.com] Coronavirus illustration (stock image).

Credit: (c) dermatzke / stock.adobe.com [Coronavirus illustration |
Credit: (c) dermatzke / stock.adobe.com] Coronavirus illustration
(stock image).

Credit: (c) dermatzke / stock.adobe.com Close SARS-CoV-2, the coronavirus causing the global COVID-19 pandemic, uses a protein called polymerase
to replicate its genome inside infected human cells.

Terminating the polymerase reaction will stop the growth of the
coronavirus, leading to its eradication by the human host's immune system.


========================================================================== Researchers at Columbia Engineering 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 new study was published on June 18, 2020, in Antiviral Research.

The Columbia team 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. Led by Jingyue Ju, 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, they
then collaborated with 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 an earlier set of 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 analogues (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.

Using the molecular insight gained in these investigations, the team
devised a strategy to select 11 nucleotide analogue 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.

Prodrug medications of five of these nucleotide analogues (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. Once the potency of the drugs to inhibit viral replication in cell culture is demonstrated in future investigations,
then the candidate molecules and their modified forms may be evaluated
for the development of potential COVID-19 therapies.

"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," says Ju. "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."

========================================================================== Story Source: Materials provided by Columbia_University_School_of_Engineering_and_Applied Science. Original
written by Holly Evarts. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Steffen Jockusch, Chuanjuan Tao, Xiaoxu Li, Thomas K. Anderson,
Minchen
Chien, Shiv Kumar, James J. Russo, Robert N. Kirchdoerfer,
Jingyue Ju. A library of nucleotide analogues terminate RNA
synthesis catalyzed by polymerases of coronaviruses that cause
SARS and COVID-19. Antiviral Research, 2020; 180: 104857 DOI:
10.1016/j.antiviral.2020.104857 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/06/200630125124.htm

--- up 23 weeks, 2 hours, 39 minutes
* Origin: -=> Castle Rock BBS <=- Now Husky HPT Powered! (1337:3/111)