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The coronavirus may be new, but long ago, nature provided humans with the tools to recognize it, at least on a microscopic scale: antibodies, Y-shaped immune proteins that can attach to pathogens and prevent them from infiltrating cells. .
Millions of years of evolution have turned these proteins into the disease weapons they are today. But within a few months, a combination of human and artificial intelligence may have beaten Mother Nature at her own game.
Using computational tools, a team of researchers from the University of Washington designed and built a molecule from scratch that, when compared to the coronavirus in the laboratory, can attack and sequester it at least as an antibody does. When sprayed on the noses of mice and hamsters, it also appears to protect animals from becoming seriously ill.
This molecule, called a mini-ligand for its ability to attach to the coronavirus, is small and stable enough to be shipped en masse in a freeze-dried state. Bacteria can also be engineered to churn out these mini-binders, potentially making them not only effective but also cheap and affordable.
The team’s product is still in the very early stages of development and won’t be on the market anytime soon. But so far it “looks very promising,” said Lauren Carter, one of the researchers behind the project, which is led by biochemist David Baker. Eventually, healthy people may be able to self-administer the mini-binders as a nasal spray and potentially keep any incoming coronavirus particles at bay.
“The sleekest app might be something you keep on your nightstand,” said Dr. Carter. “It’s kind of a dream.”
Mini-binders are not antibodies, but they fight the virus in substantially similar ways. The coronavirus enters a cell using some sort of key and key interaction, inserting a protein called spike – the key – into a molecular block called ACE-2, which adorns the exterior of some human cells. Antibodies produced by the human immune system can interfere with this process.
Many scientists hope that the mass-produced imitations of these antibodies can help cure people with Covid-19 or prevent them from getting sick after being infected. But a lot of antibodies are needed to keep coronavirus in check, especially if an infection is ongoing. Antibodies are also burdensome to produce and supply to people.
To develop a less fussy alternative, members of the Baker lab, led by biochemist Longxing Cao, took a computational approach. The researchers modeled how millions of hypothetical lab-designed proteins might interact with the peak. After sequentially eliminating the underperforming artists, the team selected the best of the bunch and synthesized them in the lab. They spent weeks alternating between the computer and the desk, tinkering with blueprints to match simulation and reality as closely as possible.
The result was a completely homemade mini-binder that easily bonded to the virus, the team reported in Science last month.
“This goes beyond just building natural proteins,” said Asher Williams, a Cornell University chemical engineer who was not involved in the research. If adapted for other purposes, Dr. Williams added, “this would be a big win for bioinformatics.”
The team is now tinkering with deep learning algorithms that could teach the lab’s computers to simplify the iterative trial-and-error process of protein design, producing products in weeks rather than months, Dr. Baker said.
But the novelty of the mini-binder approach could also be a disadvantage. It is possible, for example, that the coronavirus could mutate and become resistant to the DIY molecule.
Daniel-Adriano Silva, a biochemist at Seattle-based biopharmaceutical company Neoleukin who previously trained with Dr. Baker at the University of Washington, may have devised another strategy that could solve the resistance problem.
His team also designed a protein that can stop the virus from invading cells, but their DIY molecule is slightly more familiar. It’s a smaller, more robust version of the human ACE-2 protein, one that has a much stronger grip on the virus, so the molecule could potentially act as a lure that lures the pathogen away from vulnerable cells.
Developing resistance would be pointless, said Christopher Barnes, a structural biologist at the California Institute of Technology who collaborated with Neoleukin on their project. A strain of coronavirus that could no longer be bait-bound would also likely lose its ability to bind to the real thing, the human version of ACE-2. “This is a big fitness cost to the virus,” said Dr. Barnes.
Mini-collectors and ACE-2 baits are both easy to make and likely cost only pennies compared to synthetic antibodies, which can carry price tags in the thousands of dollars, Dr. Carter said. And while antibodies must be kept cold to preserve longevity, DIY proteins can be designed to work well at room temperature or even more extreme conditions. The University of Washington mini-binder “can be boiled and it’s still OK,” said Dr. Cao.
Such durability makes these molecules easy to transport and easy to administer in various ways, perhaps by injecting them into the bloodstream as a treatment for an ongoing infection.
The two designer molecules also both engage the virus in super tight compression, allowing less to do more. “If you have something that binds this well, you don’t have to use as much of it,” said Attabey Rodríguez Benítez, a biochemist at the University of Michigan who was not involved in the research. “This means you are getting more money for your money.”
Both research groups are exploring their products as potential tools not only to fight infections but also to prevent them completely, a bit like a short-lived vaccine. In a series of experiments described in their article, Neoleukin’s team misted their ACE-2 bait into the hamsters’ noses, then exposed the animals to the coronavirus. The untreated hamsters became seriously ill, but the hamsters who received the nasal spray fared much better.
Dr. Carter and her colleagues are currently conducting similar experiments with their mini-binder and are seeing comparable results.
These findings may not translate to humans, the researchers warned. And neither team has yet found a perfect way to feed their products to animals or people.
In the future, there may still be opportunities for the two types of designer proteins to work together – if not in the same product, at least in the same war, in which the pandemic is raging. “It’s very complementary,” said Dr. Carter. Hopefully, molecules like these could join the growing arsenal of public health measures and drugs already in place to fight the virus, he said: “This is another tool you may have.”
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