Scientists Identify Existing Drugs That Can Inhibit SARS-CoV-2 Virus

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The COVID-19 pandemic has caused more than 600,000 deaths in the United States since the start of 2020 and more than 4 million worldwide. The search for effective treatments for the disease is ongoing, and one of the hurdles is that SARS-CoV-2, the virus that causes COVID-19, has a number of molecular tricks up its sleeve when it comes down to it. it’s about infecting people.

In a recent study published in Nature Communications Biology, researchers at the U.S. Department of Energy’s (DOE) Argonne National Laboratory and the University of Chicago identified a way to interfere with a sneaky mechanism the virus uses. to prevent an immune system response from an infected person. .

These structures will almost certainly be used by many other researchers to design additional antiviral agents. “

Karen Anderson, Yale University

This new weapon against COVID-19 actually comes from the fight against cancer, as scientists have found that tipiracil, a drug used to treat colorectal cancer, can inhibit the action of one of the main proteins that make up SARS-CoV-2.

SARS-Cov-2 is a ribonucleic acid (RNA) virus. RNA is a type of genetic code that can be translated into proteins that allow the virus to replicate. During its RNA duplication, the virus would usually have a distinct chemical genetic signature -; a chain of molecules, or bases, that add to one end of the SARS-CoV-2 RNA backbone.

This chemical signature would normally be recognizable by the body and elicit an immune response, but the virus has a special way of hiding the extra molecules and sneaking around the body undetected. The research team used resources from the Advanced Photon Source (APS), a user facility at the DOE Office of Science in Argonne, to test a new processing option that could circumvent this mechanism.

The research was led by Andrzej Joachimiak d’Argonne and the University of Chicago, along with Argonne protein crystallographer Youngchang Kim and University of Chicago structural biologist Natalia Maltseva and their colleagues. Joachimiak is the director of the Center for Structural Biology (SBC) at APS, and the research team used the high-powered x-ray beams generated there to study one of the virus’s proteins, called Nsp15.

This protein acts like a molecular scissor, cutting off regions of the virus that are involved in its ability to reproduce. As more and more of these chains of molecules -; consisting of uridine, one of the main components of nucleic acid -; are produced, the Nsp15 molecule suppresses them, essentially giving the virus the haircut it needs to go unnoticed.

“Not all of the functions of these proteins are fully understood yet, but some of them serve to cut the larger poly-protein into smaller functional units. The RNA gives you the template and the encoded proteins act like scissors. “said Joachimiak.

The virus uses uridine chains to duplicate itself and translate these copies into proteins. These uridine chains would usually create an immune response, but the Nsp15 cuts it, allowing the virus to proliferate and the infection to spread. Tipiracil inhibits the action of Nsp15 by binding to where Nsp15 would otherwise.

In addition to tipiracil, another drug used for an entirely different disease may have applications in the treatment of COVID-19.

Scientists at Yale University used APS to study the structure of the anti-seizure drug perampanel as a starting point for the design of inhibitors. Modifying perampanel to create new drug configurations has given researchers new molecules effective against SARS-CoV-2. These new molecules would be used with remdesivir, a current therapeutic agent for COVID-19.

Yale researchers William Jorgensen and Karen Anderson used a combination of x-rays and computers to target the major protease SARS-CoV-2, a key enzyme that plays an important role in COVID-19 infection. Perampanel was one of 14 drugs identified from a virtual screening effort to discover potential inhibitors of SARS-CoV-2, from an initial investigation of around 2,000 known drugs. The research team found that these new analogues of perampanel were effective against the major protease, especially when combined with remdesivir.

The results of their research have been published by the American Chemical Society.

“These structures will almost certainly be used by many other researchers to design additional antiviral agents,” said Karen Anderson, professor of pharmacology and molecular biophysics and biochemistry at Yale, and co-director of developmental therapies for the Yale Cancer Center and William Jorgensen. , Sterling professor of chemistry in the chemistry department at Yale.

Source:

Journal reference:

Kim, Y., et al. (2021) Tipiracil binds to the uridine site and inhibits SARS-CoV-2 endoribonuclease Nsp15 NendoU. Communication biology. doi.org/10.1038/s42003-021-01735-9.


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