A new method for generating binding proteins solves a long-standing challenge in drug development

A team of scientists has created a powerful new method for generating protein drugs. Using computers, they designed molecules that could target important proteins in the body, such as the insulin receptor, as well as vulnerable proteins on the surface of viruses. This solves a longstanding challenge in drug development and may lead to new treatments for cancer, diabetes, infection, inflammation and beyond.

The research, published on March 24 in the journal Naturewas led by scientists from the lab of David Baker, professor of biochemistry at the University of Washington School of Medicine and recipient of the 2021 Breakthrough Prize in Life Sciences.

The ability to generate new proteins that bind tightly and specifically to any molecular target you want is a paradigm shift in drug development and molecular biology more broadly.”

David Baker, Professor of Biochemistry, University of Washington School of Medicine

Antibodies are the most common protein-based drugs today. They generally work by binding to a specific molecular target, which then either becomes activated or deactivated. Antibodies can treat a wide range of health conditions, including COVID-19 and cancer, but generating new ones is a challenge. Antibodies can also be expensive to manufacture.

A team led by two Baker lab postdoctoral researchers, Longxing Cao and Brian Coventry, has combined recent advances in the field of computational protein design to arrive at a strategy for creating new proteins that bind to molecular targets in a way similar to antibodies. They developed software that can scan a target molecule, identify potential binding sites, generate proteins targeting those sites, and then screen millions of candidate binding proteins to identify those most likely to work.

The team used the new software to generate high-affinity binding proteins against 12 distinct molecular targets. These targets include important cellular receptors such as TrkA, EGFR, Tie2, and the insulin receptor, as well as proteins on the surface of influenza virus and SARS-CoV-2 (the virus that causes COVID-19). 19).

“When it comes to creating new drugs, there are soft targets and hard targets,” said Cao, who is now an assistant professor at Westlake University. “In this article, we show that even very hard targets lend themselves to this approach. We were able to make proteins binding to certain targets that had no known binding partners or antibodies,”

In total, the team produced more than half a million candidate binding proteins for the 12 selected molecular targets. The data collected on this large pool of candidate binding proteins was used to improve the overall method.

“We look forward to seeing how these molecules could be used in a clinical setting, and more importantly, how this novel method of protein drug design could lead to even more promising compounds in the future,” Coventry said.

The research team included scientists from the University of Washington School of Medicine, Yale University School of Medicine, Stanford University School of Medicine, Ghent University, the Scripps Research Institute and the National Cancer Institute, among other institutions.

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