“God Forbid We Need This, but We Will Be Ready” – Scientists Prepare for Next Coronavirus Pandemic, Maybe in 2028?

New drug target found for future and current coronaviruses.

Scientists are already preparing for a possible next coronavirus pandemic to strike, following the seven-year pattern since 2004.

In forward-looking research, scientists at Northwestern University Feinberg School of Medicine have identified a new target for a drug to treat SARS-CoV-2 that could also affect a newly emerging coronavirus.

“God forbid we need this, but we’ll be ready,” said Karla Satchell, a professor of microbiology-immunology at Feinberg, who leads an international team of scientists to analyze the virus’s important structures. The Northwestern team previously mapped the structure of a virus protein called nsp16, which is present in all coronaviruses. This new study provides crucial information that could aid drug development against future coronaviruses and SARS-CoV-2.

“There is a great need for new approaches to drug discovery to combat the SARS-CoV-2/COVID-19 pandemic and infections from future coronaviruses,” Satchell said.

“The idea is that this future drug would work early in the infection,” Satchell said. “If someone around you gets the coronavirus, you run to the drugstore to get your medicine and take it for three or four days. If you were sick, you wouldn’t get so sick.”

The article was published in Science Signaling.

Satchell’s team mapped or “dissolved” three new protein structures in three-dimensional representations and discovered a secret identifier in the machine that helps the virus hide from the immune system.

They discovered a coronavirus-specific pocket in the protein, nsp16, that binds the virus genomic fragment held in place by a metal ion. The fragment is used by the coronavirus as a template for all viral building blocks.

For this reason, Satchell said, there is potential to create a drug that fits into this unique pocket that would block the function of this coronavirus protein. It would not block the function of a similar protein from human cells that lack the pocket. Such a drug would therefore only target the invader protein.

Nsp16 is considered one of the most important viral proteins that can be inhibited by drugs to stop the virus shortly after a person is exposed. The goal is to stop the virus early before people get too sick. Because little research has been done on nsp16, Satchell’s team has been working to generate important information about this protein and is collaborating with chemists who will use the information to design drugs against the protein.

While some of the coronavirus proteins vary widely, nsp16 is nearly the same for most. The unique pouch discovered by Satchell’s group is present in all different members of the coronavirus. This means that drugs designed to fit in this pocket should work against all coronaviruses, including one that emerges in the future. And it should work against the common cold caused by a coronavirus.

Satchell imagines that any drug developed based on her team’s discovery of the coronavirus would be part of a treatment cocktail that patients would take early in the course of the disease. Those could be drugs similar to Remdesivir, a drug that prevents the virus from making the template for the building blocks it needs to replicate itself.

The team behind the discovery

The Northwestern team at the Center for Structural Genomics of Infectious Diseases (CSGID) expressed, purified and crystallized this protein. The idea of ​​the project came from first study author George Minasov, associate professor of microbiology-immunology at Feinberg. He collaborated with Feinberg research associate professor Ludmilla Shuvalova to crystallize the protein and also with postdoctoral colleague Monica Rosas-Lemus, who developed an assay to test the protein’s function based on information from its structure.

The team collaborated with Purdue University researcher Andrew Mesecar, who helped with biochemical assays. Data on the structure was collected by the Life Sciences Collaborative Access Team at the Advanced Photon Source of Argonne National Laboratories by Joseph Brunzelle. Minasov solved the structure from the collected data.

This project is one of many undertaken by the CSGID to use structural biology to understand the biology of the virus responsible for the COVID-19 pandemic. Overall, the center has made significant contributions to the development of vaccines, drugs, and diagnostics. The international team has solved more than 70 different viral structures to reveal viral protein structure, interactions with potential drugs, and interactions with antibodies. This work is made available free of charge to the global community to accelerate efforts to design novel coronavirus treatments to combat COVID-19 and future pandemics.

Reference: “Mn2+ coordinates Cap-0 RNA to align substrates for efficient 2′-O-methyl transfer by SARS-CoV-2 nsp16″ by George Minasov, Monica Rosas-Lemus, Ludmilla Shuvalova, Nicole L. Inniss, Joseph S Brunzelle, Courtney M. Daczkowski, Paul Hoover, Andrew D. Mesecar, and Karla JF Satchell, June 29, 2021, Science Signaling.
DOI: 10.1126/scisignal.abh2071

The CSGID is supported by a contract from the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, in part to serve as a response site to conduct structural biology research in the event of an unexpected infectious disease outbreak. NIAID has been working closely with the Center since early January to coordinate the Center’s activities with other research supported by the NIAID to enable drug discovery.

This study was funded by contract HHSN272201700060C from NIAID.