Promising Molecule Holds Potential for Slowing Down COVID-19

Scientists have made an exciting discovery with the development of a molecule equipped with specialized hooks that can effectively disable a troublesome protease found in the SARS-CoV-2 virus. This breakthrough molecule shows great promise in combating infections caused by the virus.

The protease, known as PLpro, is a dangerous enzyme produced by SARS-CoV-2, aiding in its replication while simultaneously disabling the immune system’s communication network. By engineering a molecule capable of mitigating the harmful effects of this potent protease, researchers have taken a significant step forward in fighting against the virus.

While there is still much work ahead before this molecule can be transformed into a viable drug, scientists now have a glimpse of what the future drug may look like, thanks to the latest images revealing the molecule bound to the protease.

“This discovery of an effective molecule has been a long-awaited breakthrough,” stated Suman Pokhrel, a lead author of the study and a graduate student in chemical and systems biology at Stanford University. “Being part of the team that made this discovery is truly exciting, as it opens up the possibility of developing a new antiviral drug for treating COVID-19.”

To visualize the atomic structure of the molecule interacting with the protease, researchers employed bright X-rays generated by the Stanford Synchrotron Radiation Lightsource (SSRL) at the SLAC National Accelerator Laboratory, a facility operated by the Department of Energy. These X-rays enabled the team to observe precisely how the molecule binds to the protease. The research findings, published in Nature Communications, were the result of collaboration among scientists from SLAC, Stanford University, Oak Ridge National Laboratory, and other institutions.

Jerry Parks, senior scientist at Oak Ridge National Laboratory and project leader, explained, “Using computational approaches, we designed molecules and predicted their interactions with the enzyme. Our collaborators from universities and industry tested these molecules experimentally to confirm their effectiveness. Finally, the crystal structure was solved at SLAC, confirming our predictions. This step is crucial as we continue to enhance the molecule.”

Overcoming the challenges associated with targeting the protease proved to be a demanding task. Unlike another primary protease called Mpro, PLpro has a narrow groove and a highly flexible structure, making it difficult to crystallize. However, crystal samples are vital in designing modern medicine.

Pokhrel emphasized the significance of obtaining a crystal sample, stating, “Without a crystal sample, it would be impossible to obtain a clear picture of PLpro. And without knowing its structure, it becomes extremely challenging to develop drugs to inhibit it. Although one can attempt to design a drug blindly, it is much more difficult without a clear understanding of its structure.”

Creating the crystal required a combination of patience, persistence, and good fortune, as explained by Soichi Wakatsuki, a professor at SLAC and Stanford and co-senior author of the study. He expressed, “Obtaining the protease and molecule crystal was a significant breakthrough in our efforts. Now we can continue modifying the molecule to enhance its binding to PLpro.”

The distinctive shape of PLpro necessitated the development of a molecule tailored to fit its narrow groove precisely. The researchers started with an existing compound known as GRL0617 and extended it to include a slender portion with a chemical group capable of forming a permanent bond with the protein. By exploring various extensions, the team transformed the original molecule into a shape that tightly latches onto PLpro, with ongoing efforts aimed at further improving its design.

Brian Sanders, a chemist at Oak Ridge National Laboratory and lead author of the study, explained, “We took an existing compound and modified it to enhance its affinity for PLpro. We are now working on creating even better compounds that can be taken orally and are more resistant to degradation in the body.”

While the new molecule successfully slowed down the protein-cutting activity of PLpro, several crucial questions remain to be answered before it can be developed into an antiviral drug. One of the key concerns is ensuring that the drug does not interfere with similar beneficial proteins in the human body.

Kaur, a Stanford undergraduate student and research project intern, cautioned, “Many proteins in our body perform functions similar to PLpro, so we must exercise caution to avoid blocking those proteins. This challenge highlights the complexity of our efforts.”

Nonetheless, the research results have instilled confidence in the team regarding their ability to design drugs for future viruses, thanks to the processes developed through the study of PLpro. The collaboration among experts from various Department of Energy national labs and universities has been instrumental in their progress. This collaborative approach could prove invaluable in the future when identifying novel prototypes or modifying known prototype molecules to enhance their effectiveness against emerging viruses.

“While the molecule we are using to target PLpro may not be effective against other viruses, the processes we have developed are immensely valuable,” Pokhrel stated. “This approach could be applied to develop antiviral drugs to combat future outbreaks.”

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More about COVID-19 antiviral drugs

• Nature Communications – The research paper published in Nature Communications.
• Stanford Synchrotron Radiation Lightsource (SSRL) – The website for the Stanford Synchrotron Radiation Lightsource, which provided the X-rays for visualizing the molecular interaction.
• SLAC National Accelerator Laboratory – The official website of SLAC National Accelerator Laboratory, where the crystal structure was solved.
• Oak Ridge National Laboratory – The website for Oak Ridge National Laboratory, where researchers collaborated in designing and testing the molecule.
• Department of Energy – The official website of the U.S. Department of Energy, which provided funding and support for the research project.