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Antibodies Good. Machine-made molecules better?



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

Millions of years of evolution have honed these proteins into the disease-fighting weapons they are today. But in a matter of months, a combination of human and machine intelligence may have beaten Mother Nature in its own game.

Using computational tools, a team of researchers at the University of Washington designed and built from scratch a molecule that, when placed against coronavirus in the laboratory, can attack and sequester it at least as well as an antibody does. When you spray your nose on mice and hamsters, it also seems to protect animals from becoming seriously ill.

This molecule, called a mini-binder because of its ability to adhere to the coronavirus, is petite and stable enough to be sent en masse in a freeze-dried state. Bacteria can also be engineered to smooth out these mini-binders, potentially making them not only effective but also inexpensive and practical.

The team’s product is still in the very early stages of development and will not hit the market 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 may self-administer the mini-binders as a nasal spray and potentially keep any constituent coronavirus particles at bay.

“The most elegant application may be something you keep on your bedside table,” said Dr. Carter. “It’s a kind of dream.”

Mini-binders are not antibodies, but they counteract the virus in much similar ways. Coronavirus enters a cell through a kind of lock-and-key interaction that matches a protein called a spike – the key – in a molecular lock called ACE-2, which adorns the outside of certain human cells. Antibodies produced by the human immune system can interfere with this process.

Many researchers hope that mass-produced imitations of these antibodies can help treat people with Covid-19 or prevent them from becoming ill after being infected. However, many antibodies are needed to clear the coronavirus, especially if an infection is ongoing. Antibodies are also cumbersome to produce and deliver to humans.

To develop a less sinister alternative, members of the Baker lab, led by biochemist Longxing Cao, took a computational method. The researchers modeled how millions of hypothetical, laboratory-designed proteins would interact with the tip. After sequentially eradicating bad artists, the team selected the best among the flock and synthesized them in the laboratory. They spent weeks switching between the computer and the bench and tinkering with designs to match simulation and reality as closely as possible.

The result was a completely homemade mini-binder that easily glued to the virus, the team at Science reported 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 is adapted for other purposes, Dr. added. Williams, “it would be a great gain for bioinformatics.”

The team is now tinkering with deep-learning algorithms that could teach lab computers to streamline the iterative trial-and-error process of protein design, delivering products in weeks instead of months, said Dr. Baker.

But the novelty of the mini-binding method could also be a disadvantage. For example, it is possible that coronavirus can mutate and become resistant to the DIY molecule.

Daniel-Adriano Silva, biochemist at Seattle-based biopharmaceutical company Neoleukin, who previously trained with Dr. Baker at the University of Washington, may have come up with another strategy that could solve the resistance problem.

His team has also designed a protein that can stop the virus from attacking cells, but their DIY molecule is a little more well-known. It is a smaller, more robust version of the human protein ACE-2 – one that has a much stronger grip on the virus so that the molecule can potentially serve as a lure that lures the pathogen away from vulnerable cells.

Developing resistance would be useless, said Christopher Barnes, a structural biologist at the California Institute of Technology who collaborated with Neoleukin on their project. A coronavirus strain that could no longer be bound by the lid would probably also lose its ability to bind to the real thing, the human version of ACE-2. “It’s a big fitness cost for the virus,” said Dr. Barnes.

Mini-binders and ACE-2 decoys are both easy to manufacture and probably cost only a penny on the dollar compared to synthetic antibodies, which can carry price tags in the big thousands of dollars, said Dr. Carter. And while antibodies need to be kept cold to maintain longevity, DIY proteins can be engineered to do just fine at room temperature or in even more extreme conditions. The University of Washington mini-binder “can be boiled and it’s still OK,” said Dr. Cao.

This shelf life makes these molecules easy to transport and easy to administer in a variety of ways, perhaps by injecting them into the bloodstream as a treatment for an ongoing infection.

The two designer molecules also both involve the virus in a super-tight press, giving less opportunity to do more. “If you have something that binds this well, you do not need to spend that much,” said Attabey Rodríguez Benítez, a biochemist at the University of Michigan who was not involved in the research. “It means you get more out of your money.”

Both research groups are exploring their products as potential tools, not only to fight infection, but also to prevent it directly, just like a short-term vaccine. In a series of experiments described in their paper, the Neoleukin team dropped their ACE-2 decoy into the noses of hamsters and then exposed the animals to coronavirus. The untreated hamsters became dangerously ill, but the hamsters that received the nasal spray did much better.

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

These findings may not translate into humans, the researchers warned. And none of the teams have yet devised a perfect way to administer their products to animals or humans.

Down the line, there may still be opportunities for the two types of designer proteins to work together – if not in the same product, then at least in the same war that the pandemic is raging. “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 already in place to fight the virus, she said: “This is another tool you could have.”

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