Coronavirus may be new, but nature has long since provided humans with the tools to identify it, at least on a microscopic scale: antibodies, Y-shaped immune proteins that can lurk on pathogens and block them from invading cells.
Millions of years of evolution have turned this protein into a disease-fighting weapon nowadays. But in just a matter of months, a combination of human and machine intelligence could beat Mother Nature in her own game.
Using computational tools, a team of researchers from the University of Washington designed and built a molecule that can attack coronaviruses in labs and, at least, antibodies. When scattered over the noses of mice and hamsters, it also appears to protect animals from serious illness.
This molecule, called a mini-binder for its ability to gloss over coronaviruses, is a very fine and stable particle that is sent to the mass in a stable-dry state. Bacteria can also be engineered to churn this mini-binder, potentially making it not only effective, but also cheap and convenient.
The team’s product is still in the very early stages of development, and will not be on the market anytime soon. But so far “it looks very promising,” said Lauren Carter, one of the researchers behind the project, led by biochemist David Baker. Eventually, healthy people will be able to self-administer mini-binders as a nasal spray and potentially keep any inland coronavirus particles at bay.
Dr. Carter said, “The most beautiful app is something you put on the table next to your bed. “It’s kind of a dream.”
Mini-binders are not antibodies, but they fail the virus equally widely. The coronavirus enters the cell using a type of lock-and-key interaction, fitted with a protein called spike-key, which is implanted in a molecule called ACE-2, which adorns the outside of certain human cells. Antibodies produced by the human immune system can interfere with this process.
Many scientists hope that mass-produced copies of these antibodies will help treat people with covid-19 or prevent them from becoming ill after becoming infected. But many antibodies are needed to control the coronavirus, especially if the infection persists. Antibodies are also hard to produce and deliver to people.
In order to develop a less Finicky alternative, members of the Baker Lab, led by biochemist Longxing Cao, adopted a computational approach. The researchers modeled how millions of imaginary, lab-designed proteins would interact with the spike. After gradually weeding out the weak performers, the team made the best choice between the bunch and synthesized them in the lab. They spent weeks galloping between the computer and the bench, tincturing with simulations and designs to match reality as closely as possible.
The result was a completely homemade mini binder that easily glued itself to the virus, the team reported in Science last month.
“This is one step further than just shutting down natural proteins,” said Asher Williams, a chemical engineer at Cornell University who is not involved in the research. If accepted for other purposes, Dr. Williams added, “This would be a big win for bioinformatics.”
Dr. B. Baker said the team is now merging with deep-learning algorithms that allow lab computers to produce products in weeks instead of months, to streamline the repeated testing and error processing of protein designs.
But the novelty of the mini-binder approach can also be a drawback. For example, it is possible that the coronavirus may change and become resistant to the DIY molecule.
Daniel-Adriano Silva, a biochemist at Seattle-based biopharmaceutical company Neolukin, who previously trained with Dr. Baker at Washington University in Washington, could come up with another strategy that could solve the resistance problem.
His team has also developed a protein that can prevent viruses from invading, but their DYY molecule is a little more familiar. It is a smaller, unreliable version of the human protein ACE-2 – which has a stronger grip on the virus, so the molecule can potentially serve as a compressor that keeps pathogens away from sensitive cells.
Christopher Barnes, a structural biologist at the California Institute of Technology, said those who partnered with Neolukin on his project would be futile to develop that resistance. A coronavirus strain that can no longer be bound by decoy will probably also lose the ability to bind with the human version of the real thing, ACE-2. “It’s a big fitness cost for the virus,” Dr. Barnes said.
Mini-binders and ACE-2 decoys are both easier to make, and are likely to cost only pennies per dollar compared to synthetic antibodies, which can cost tens of thousands of dollars. Said Carter. Antibodies must be kept cold to preserve longevity, while DIY proteins can be engineered to cool at room temperature, or even in more extreme conditions. “The University of Washington’s mini-binder can be boiled and it’s still fine,” said Dr. Cao.
That durability makes these molecules easier to transport and easier to manage in a variety of ways, perhaps by injecting them into the bloodstream to treat an ongoing infection.
Both designer molecules also engage the virus in a super-tight squeeze, causing more or less. “If you have something that binds this well, you don’t need to use it as much,” said Atabe Rodriguez Benatez, a biochemist at the University of Michigan who was not involved in the research. “That means you’ll get more bang for your buck.”
Both research groups are exploring their products as potential tools not only to fight the infection, but also to prevent it altogether, somewhat like a short-term vaccine. In a series of experiments described in their paper, the Neolukin team incorrectly injected their ACE-2 decoy into a hamster’s nose, then exposed the animals to coronavirus. Untreated hamsters became dangerously ill, but hamsters receiving nasal sprays remained very good.
Dr. Carter and his colleagues are currently conducting similar experiments with their mini-binder, and are seeing comparable results.
Researchers warn that these findings do not translate into humans. And no team has yet created a great way to manage their products in animals or people.
Below the line, there may still be opportunities to work with two types of designer proteins – if they are not in the same product, at least in the same war, the epidemic will break out. “It’s very complementary,” said Dr. Carter said. If all goes well, molecules like these could join the growing arsenal of public health measures and drugs instead of fighting the virus, she said: “This is another tool you can do.”
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