Antibodies Good. Machine-Made Molecules Higher?

Antibodies Good. Machine-Made Molecules Better?

The coronavirus may be new, but nature long ago gave humans the tools to recognize it, at least on a microscopic scale: antibodies, Y-shaped immune proteins that can bind to pathogens and prevent them from infiltrating cells.

Millions of years of evolution have made these proteins the disease-fighting weapons they are today. But in just a few months, a combination of human and machine intelligence could have beaten Mother Nature in her own game.

Using computing tools, a team of researchers from the University of Washington designed and built a molecule from scratch that, when faced with the coronavirus in the laboratory, can attack and bind it at least as well as an antibody. When it splashes the noses of mice and hamsters, it appears to protect animals from serious illness as well.

This molecule, known as a mini-binder because of its ability to adhere to the coronavirus, is small and stable enough to be shipped in bulk when it is freeze-dried. Bacteria can also be engineered to produce these mini-binders, which may make them not only effective but also cheap and convenient.

The team's product is still in a very early stage of development and will shortly be no longer on the market. "So far, however, it looks very promising," said Lauren Carter, one of the researchers behind the project, which is led by biochemist David Baker. After all, healthy people may be able to administer the mini-binders themselves as a nasal spray and possibly keep incoming coronavirus particles at bay.

"The most elegant application could be something you keep on your bedside table," said Dr. Carter. "It's kind of a dream."

Mini-binders are not antibodies, but they thwart the virus in much similar ways. The coronavirus enters a cell through a type of lock-and-key interaction and fits a protein called spike – the key – into a molecular lock called ACE-2, which adorns the outside of certain human cells. Antibodies made by the human immune system can interfere with this process.

Many scientists hope that mass-produced mimickers of these antibodies could help treat people with Covid-19 or prevent them from getting sick after an infection. However, many antibodies are needed to contain the coronavirus, especially when an infection is underway. Antibodies are also difficult to produce and deliver to humans.

In order to develop a less delicate alternative, members of the Baker laboratory, led by biochemist Longxing Cao, took a computational approach. The researchers modeled how millions of hypothetical, laboratory-designed proteins would interact with the tip. After the top performers were singled out one by one, the team selected the best and pooled them in the laboratory. They spent weeks switching between computer and bank, tinkering with designs that match simulation and reality as closely as possible.

The result was an all-homemade mini-binder that easily stuck to the virus, the team reported in Science last month.

"This goes a step further than just building natural proteins," said Asher Williams, a chemical engineer at Cornell University who was not involved in the research. If it were adapted for other purposes, Dr. Williams added, "it would be a great asset to bioinformatics."

The team is now playing with deep learning algorithms that can help the lab's computers learn to streamline the iterative trial-and-error process of protein design and get products in weeks instead of months, said Dr. Baker.

The novelty of the mini-binder approach could also be a disadvantage. For example, it is possible that the coronavirus may mutate and act against the D.I.Y. Molecule.

Daniel-Adriano Silva, biochemist at Seattle-based biopharmaceutical company Neoleukin, who previously worked for Dr. Baker, who was trained at the University of Washington, may have devised another strategy that might solve the resistance problem.

His team has also developed a protein that can prevent the virus from entering cells, but preventing their D.I.Y. Molecule is a little more familiar. It's a smaller, more robust version of the human protein ACE-2 – one that the virus has far more under control, so the molecule can potentially act as a bait to lure the pathogen away from vulnerable cells.

Developing resistance would be pointless, said Christopher Barnes, a structural biologist at the California Institute of Technology who worked with Neoleukin on his project. A strain of coronavirus that could no longer be tied to the bait would likely also lose its ability to bind to the real thing, the human version of ACE-2. "That's a big fitness cost for the virus," said Dr. Barnes.

Mini binders and ACE-2 bait are both easy to make and likely only cost a few cents per dollar compared to synthetic antibodies, which can carry thousands of dollars' worth of price tags, said Dr. Carter. And while antibodies need to be kept cold to maintain longevity, the D.I.Y. Proteins can be engineered to function properly at room temperature or under more extreme conditions. The University of Washington mini-binder "can be boiled and is still fine," said Dr. Cao.

This shelf life makes these molecules easy to transport and administer in a variety of ways, possibly by injecting them into the bloodstream to treat persistent infection.

The two designer molecules also bind the virus very closely together so that less can do more. "When you have something that binds this well, you don't have to use that much," said Attabey Rodríguez Benítez, a biochemist at the University of Michigan who was not involved in the research. "That means you get more for your money."

Both research groups are investigating their products as potential tools not only to fight infections, but also to prevent them directly, similar to a short-lived vaccine. In a series of experiments described in their article, the Neoleukin team sprayed their ACE-2 bait with the noses of hamsters and then exposed the animals to the coronavirus. The untreated hamsters got dangerously ill, but the hamsters that received the nasal spray did far better.

Dr. Carter and her colleagues are currently doing similar experiments with their mini-binder and are seeing comparable results.

These results could not be transferred to humans, warned the researchers. And no team has yet found a perfect way to deliver their products to animals or humans.

Down the line, there may still be a possibility that the two types of designer proteins could work together – if not in the same product, then at least in the same war that the pandemic rages on. "It's very complementary," said Dr. Carter. If all goes well, molecules like these could join the growing arsenal of public health measures and drugs that are already in place to fight the virus. She said, "This is another tool you might have."

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