Team designs molecule to disrupt SARS-CoV-2 infection

A team of scientists led by the Department of Energy’s Oak Ridge National Laboratory designed a molecule that disrupts the infection mechanism of the SARS-CoV-2 coronavirus and could be used to develop new treatments for COVID-19 and other viral diseases.

Oak Ridge National Laboratory led a team of scientists to design a molecule that disrupts the infection mechanism of the SARS-CoV-2 coronavirus and could be used to develop new treatments for COVID-19 and future virus outbreaks. Photo: Michelle Lehman/ORNL, U.S. Dept. of Energy

The molecule targets a lesser-studied enzyme in COVID-19 research, PLpro, that helps the coronavirus multiply and hampers the host body’s immune response. The molecule, called a covalent inhibitor, is effective as an antiviral treatment because it forms a strong chemical bond with its intended protein target.

“We’re attacking the virus from a different front, which is a good strategy in infectious disease research,” said Jerry Parks, who led the project and leads the Molecular Biophysics group at ORNL.

The research turned a previously identified noncovalent inhibitor of PLpro into a covalent one with higher potency, Parks said. Using mammalian cells, the team showed that the inhibitor molecule limits replication of the original SARS-CoV-2 virus strain as well as the Delta and Omicron variants.

The ORNL scientists used computational modeling to predict whether their designs would effectively bind to the enzyme and disrupt its function. They then synthesized the molecules and tested them at ORNL and partner company Progenra to confirm their predictions.

The protein was expressed and purified using the capabilities of the Center for Structural Molecular Biology at the Spallation Neutron Source, or SNS, at ORNL. The bright X-rays generated by the Stanford Synchrotron Radiation Lightsource, or SSRL, at SLAC National Accelerator Laboratory were used to map the molecule and examine the binding process at an atomic level, validating the simulations.

Partners at the University of Tennessee Health Science Center and Utah State University performed the testing on mammalian cells infected with the virus.

“We took an existing compound and made it more potent by designing it to form a new chemical bond with PLpro,” said ORNL chemist and lead author Brian Sanders. “Our efforts are now to build on what we have developed to make better compounds that could one day be taken as a pill.”

The researchers are already working on a second generation of the covalent PLpro inhibitor that is more stable and better absorbed and distributed by the body, aiming to improve its suitability as an oral drug.

The same design strategy of identifying a molecule, understanding how it binds to a target, and modifying it to make it more effective could be applied to understanding and combatting future viruses, the scientists noted.

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