Newswise – Developing new drugs that remain potent against emerging variants of COVID-19 is critical to stopping the spread of the highly contagious disease and protecting human health.

After more than two years studying SARS-CoV-2, the virus that causes COVID-19, researchers at the Department of Energy’s (DOE) Oak Ridge National Laboratory (ORNL) are now designing and testing antivirals to small molecules that block the ability of the virus. reproduce. With their collaborators at the Institut Laue-Langevin (ILL), in France, the researchers have shown that their antiviral molecules are just as effective as some of the main drugs currently on the market.

The antiviral molecules, called hybrid inhibitors, are made from repurposed drugs used to treat hepatitis C and SARS-CoV, the coronavirus that broke out in 2002.

The team’s encouraging research results, published in the journal Nature Communication, indicate that new antiviral molecules merit further development for potential use as new drugs to treat various forms of the virus.

“From the beginning, our research has revolved around the main protease, which is an enzyme inside SARS-CoV-2 that allows the virus to reproduce. If you stop the protease, you stop the virus,” said Daniel Kneller, the paper’s lead author.

The main protease of SARS-CoV-2 is shaped like a Valentine’s heart. On its surface are pockets that can bind long chains of amino acids expressed by the virus. The protease is responsible for cutting or splitting these chains, which is how the virus reproduces.

To better understand how the protease works, the researchers used a combination of X-ray and neutron experiments at ORNL’s Spallation Neutron Source (SNS) and High Flux Isotope Reactor (HFIR) to create a full three-dimensional map of each protease atom. structure. Next, they mapped the extensive network of hydrogen bonds that hold the protease together.

They also traced the location of each pocket where the cutting process occurs and discovered that the sites where amino acid chains are cut are electrically charged. Knowing the positive, negative, and neutral electrical charges of amino acid sites is essential for designing antiviral molecules that bind tightly to the protease structure. The tighter the molecules bind, the more effective they are at stopping the protease.

With the experimental data in hand, the researchers turned to study hepatitis C antiviral drugs that could potentially be redesigned, or repurposed, to block the SARS-CoV-2 protease. The team studied three Federal Drug Administration-approved hepatitis C drugs: boceprevir, narlaprevir and telaprevir. Neutron scattering experiments have revealed that the SARS-CoV-2 protease has the unique ability to change shape and alter its electrical charge states to conform to the introduced drug molecule. The unexpected discovery had not been predicted by computer simulations and provided another key piece of information about designing new drug molecules that specifically bind to the target.

put it all together

“This study is the culmination of everything we have learned so far. In it, we took the best parts of hepatitis C drugs and created three new molecules and tested them against the SARS-Cov-2 protease,” Kneller said.

Each drug molecule has what is called a warhead that binds directly to the amino acid site where the natural chemical reaction would occur. Ideally, when the warhead binds to the amino acid site, the resulting combination of enzyme and inhibitor should closely represent the natural combination.

“What we found in our previous studies is that when telaprevir binds, the warhead has a neutral charge and is actually facing the special amino acid site where the interactions would be strong,” Andrey said. Kovalevsky, senior scientist at ORNL. “So this time we designed hybrid inhibitors to provide the exact link we needed to establish close interactions between the inhibitors and the protease.”

This time, neutron scattering experiments were conducted using the LADI-DALI beamline at the ILL nuclear reactor to accelerate measurements of the molecular binding interactions between the three hybrid inhibitors and the SARS-protease. CoV-2. Because neutrons are non-destructive and very sensitive to light elements such as hydrogen, they are a powerful tool for studying complex biological processes.

“Neutrons allowed us to see for the first time these very strong binding interactions that the hybrid molecules form with the protease. These specific features of their design could be incorporated into the development of new drugs that are potentially more effective against viral replication,” said ILL Instrument Scientist Matthew Blakeley. “No other experimental technique can provide this level of detail, which is precisely what is needed to truly understand how these molecules work.”

Additional experiments were performed by researchers at the National Institutes of Health using in vitro enzyme kinetics to study inhibitors in test tube solutions. These tests also confirmed strong binding interactions, which were closely comparable to some of the leading COVID-19 drugs currently on the market.

Samples of the SARS-CoV-2 inhibitor and protease molecules used in the experiments were synthesized and developed at the Center for Nanophase Materials Sciences (CNMS) and the Center for Structural Molecular Biology at ORNL.

“We have demonstrated enormous capabilities in our ability to deliver fundamental knowledge about an emerging disease and apply it to accelerate the time to achieve effective treatments,” Kovalevsky said. “This is a big step forward not only in the fight against COVID-19, but I hope our research translates to similar challenges we may face in the future.”

Besides Kneller, Blakeley, and Kovalevsky, co-authors of the article include Hui Li, Gwyndalyn Phillips, Kevin L. Weiss, Qiu Zhang, Mark A. Arnould, Colleen B. Jonsson, Surekha Surendranathan, Jyothi Parvathareddy, Leighton Coates, John M. Louis and Peter V. Bonnesen.

Read the related articles below to learn more about the ORNL-led research campaign on the main protease of SARS-CoV-2.

SNS, HFIR and CNMS are user facilities of the DOE Office of Science. ORNL is managed by UT-Battelle for the U.S. Department of Energy’s Office of Science, the largest supporter of basic physical science research in the United States. The DOE’s Office of Science is working to address some of the most pressing challenges of our time. For more information, please visit

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