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Stanford Medicine experts help Nobel winner custom design proteins for COVID-19 therapy

Custom designing proteins — a breakthrough recognized by the latest Nobel Prize in chemistry — could yield treatments that stop the worst of COVID-19 before it begins.

The 2024 Nobel Prize in chemistry was awarded Wednesday morning to three scientists who deepened our understanding of the protein cogs and widgets that make our cells function. Those understandings have already paved the way for new research at academic medical institutions such as the Stanford School of Medicine.

One of the winners, biochemist David Baker, PhD, of the University of Washington, works frequently with several Stanford Medicine researchers. A recent collaboration, published in Nature Communications, offers an intriguing example of how the techniques honored by the Nobel committee could be used: to custom design proteins that fight severe COVID-19 infection.

"I was really excited," Stanford Medicine structural biologist Kevin Jude, PhD, said a few hours after the prize was announced. Inside the world of protein chemistry, experts have been expecting that the new Nobel laureates would receive the prize "one of these days," said Jude, adding, "I've collaborated with David on different projects over the last 10 years. He's a great guy and a great scientist."

Both Jude and Marta Borowska, PhD, are members of the lab of Chris Garcia, PhD, the Younger Family Professor and a professor of structural biology. All three scientists contributed to the study on building proteins that fight COVID-19.

"We worked on this project at the height of the pandemic, when vaccines and remedies were still limited," said Borowska, a postdoctoral scholar. "It felt urgent and meaningful. The idea that our work could help millions was incredibly motivating."

Marta Borowska, Chris Garcia and Kevin Jude

From sheet music to song

Scientists have known for decades that a protein's finished physical shape is determined by its sequence of amino acids, aka protein building blocks. But they had no way of predicting from a specific amino acid sequence what the protein's 3-D shape would actually be. This has been rather like having the sheet music sitting around for Beethoven's Fifth Symphony and knowing that the notes on the page meant "melody and harmony" with no ability to envision the sound of the opening ba-na-na-NAH.

Half of the chemistry prize recognized two scientists, Demis Hassabis and John Jumper of Google DeepMind, who developed an artificial intelligence tool called AlphaFold to decode proteins, essentially turning sheet music into song. The other half went to Baker for his work to design and build useful proteins from scratch -- to eventually become a Beethoven of proteins, as it were.

In the Nature Communications paper, researchers from Baker's and Garcia's teams put these methods to work designing small proteins intended to stop immune overreactions known as cytokine storms, and they show that the custom-built proteins function as intended.

Cytokine storms have killed many people with severe cases of COVID-19. They're the product of an out-of-control chain reaction: A few immune molecules instruct the body's cells to make more, and different varieties, of other immune molecules. That, in turn, can cause massive inflammation. When this happens in the lungs, it can become impossible for the patient to breathe.

The research team aimed to stop the chain reaction before it can get out of control. They designed little proteins, no more than 65 amino acids each, to adhere to different parts of the receptors for two key immune molecules, IL-1beta and IL-6, that help launch a cytokine storm. They hoped these so-called miniproteins would stick to the receptors firmly enough to stop IL-1beta and IL-6 from attaching to and switching on their targets.

As a potential medical treatment, miniproteins have advantages. "They're somewhere between a small-molecule drug and a large protein, such as an antibody," Jude said. The miniproteins were similar in size to some naturally occurring biological molecules such as insulin, which is 51 amino acids, but a lot bigger than small-molecule drugs and a lot smaller than, say, antibodies, which are hundreds of amino acids each.

Miniproteins share some positive traits of smaller drugs, Jude said, such as being small enough that you can project them into the lungs with an inhaler, whereas big proteins are hard to aerosolize. Miniproteins can be designed to be heat-stable, which could make them easier to ship to patients than large antibodies.

Miniproteins have other advantages, Borowksa added. "Unlike traditional small-molecule drugs, designed proteins can be specifically tailored to interact with desired molecules, making them incredibly precise," she said. They're the right size for blocking interactions between naturally occurring proteins and receptors, such as IL-1 and its receptor, meaning they are large enough to cover a physical surface area too big to be blocked by a small-molecule drug. And miniproteins can be cleared from the body quickly, whereas antibodies that suppress the immune system can have lingering effects that make patients vulnerable to subsequent infections.

Unlike traditional small-molecule drugs, designed proteins can be specifically tailored to interact with desired molecules, making them incredibly precise.

Marta Borowska

Borowska and Jude checked how tightly the miniproteins designed by Baker's lab could bind to their target receptors. Borowska also solved the crystal structure of his designs -- using traditional methods for figuring out what a folded protein looks like -- and confirmed that they closely matched the designs the Baker lab had aimed for.

Researchers on the team at the University of Washington took the work a step further and showed that the proteins acted as expected to stop IL-1beta and IL-6 damage when given to cardiac organoids -- little balls of heart cells in a dish.

There's more work needed, including studies in animal models and humans, before the custom-designed proteins can be used as medical treatments. But it's far beyond what would have been possible in the past, Jude said. Over the decade he has collaborated with Baker's lab, he has seen a lot of improvement in how accurately the scientists can predict, from the get-go, the true 3D shape and function of proteins they design.

"In earlier papers we published with David's lab, we did a lot of experimental intervention, iterative testing and redesign, to get a functional molecule," Jude said. "In the last few years, they've been much more successful at designing miniproteins that work out of the box. I think it's really exciting."

He added, "Even 10 years ago, it would have been science fiction."


Image: Immune molecules and their receptors function like locks and keys. Scientists showed they could block the "lock" (green) using a custom-designed miniprotein (in orange), so the "key" won't fit in its usual (pink) spot. This offers a new way to avert a potentially dangerous immune reaction known as a cytokine storm. (Courtesy Kevin Jude and Marta Borowska)

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