Novel COVID-19 drug blocks viral replication

Researchers at the University of Illinois Chicago have identified a potent new antiviral compound that can effectively block viral replication in human cells.

The discovery, spearheaded by the UICentre for Drug Discovery, could lead to the development of a new therapy to treat patients infected by SARS-CoV-2, the virus that causes COVID-19. The researchers say it could be a powerful new weapon in the fight against the disease, for which few proven treatments are available.

The virus requires several enzymes to produce copies of itself once it has infected a cell. One of these enzymes, known as a protease, is called PLPro.

Kiira Ratia, director of the High Throughput Screening Core at the UIC Research Resources Center, studied SARS-CoV-1, another coronavirus, in the early 2000s when she was a graduate student at UIC. In her previous research, she discovered a drug, GRL0617, that could bind to PLPro and prevent SARS-CoV-1 from replicating in cells.

In March 2020, when SARS-CoV-2 was making its way across the globe, Rui Xiong, UIC research assistant professor of pharmaceutical sciences, and Gregory Thatcher, former director of UICentre for Drug Discovery, invited Ratia to team up to revisit PLPro to identify drugs that could potentially stop SARS-CoV-2 infections.

“We used several techniques to discover potent PLPro inhibitors including high throughput drug screening, rational drug design and biomimetic-based design of PLPro inhibitors,” Xiong said.

Ratia went to work screening a chemical library of 15,000 molecules provided by the UICentre. She identified one candidate and found that GRL0617 also bound to PLpro, but only weakly.

Xiong led a team of medicinal chemists at UIC — Zhengnan Shen, Deyu Kong and Yangfeng Li — to design and synthesize chemical libraries for better PLpro inhibitors. During this process, they discovered a new binding site on the PLPro enzyme they called the BL2 groove. Ratia determined that drugs bound very well to this new site.

“Drug molecules binding to this site were slower to detach from the site, meaning that drugs targeted to the newly discovered binding site would have better antiviral activity than drugs that bound weakly,” Xiong said. “This new binding site became the focus of our attention for developing next-generation PLPro inhibitors.”

Laura Cooper, a Ph.D. candidate in the laboratory of UIC’s Lijun Rong, professor of microbiology and immunology at the College of Medicine, tested several newly designed PLPro inhibitors that targeted the new binding site and identified XR8-24 as a potent inhibitor of SARS-CoV-2 in infected monkey and human cells. Viral levels in cells treated with the drug were undetectable or exceedingly low.

“Remdesivir received approval from the FDA to treat this emerging threat, but there are better antiviral protease inhibitors to be found, and we think that XR8-24, which we have optimized in the lab over the last many months, is one of them that, together with vaccines, can help reduce deaths caused by COVID-19,” Rong said.

Michael Flavin, interim director of the UICentre for Drug Discovery, says that XR8-24 might be used as part of a drug cocktail to treat COVID-19 that could include remdesivir, which binds to the viral RNA polymerase.

“Together, our drug and other protease inhibitors could have a very powerful effect on stopping SARS-CoV-2 replication in the body and preventing or treating this devastating disease,” Flavin said.

“The UICentre for Drug Discovery helped the researchers working on this drug to develop the tests needed to determine its ability to block viral replication and provided the tools to modify the original drug candidate to make it more effective,” he said. “The researchers also used our x-ray crystallography expertise to help create 3-dimensional models of the drug that helped in improving the binding properties of the drug.”

The findings have been posted to BioRxiv, a free online archive and distribution service for unpublished preliminary reports in the life sciences. Papers posted to BioRxiv have yet not been peer-reviewed or accepted to a journal.

Also contributing to this work, which is support by a grant from the National Institute of Health (UL1TR002003) are UIC’s Hyun Lee, Youngjin Kwon, Saad Alqarni, Fei Huang and Oleksii Dubrovskyi.

Written by Sharon Parmet