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Antibodies Good. Better machine molecules?



The coronavirus may be new, but nature has long given humans the tools to recognize it, at least on a microscopic scale: antibodies, Y-shaped immune proteins that can attach to pathogens and block them from penetrating cells.

Millions of years of evolution have perfected these proteins in weapons to fight disease as they are today. But in just a few months, a combination of human and machine intelligence may have defeated Mother Nature in her own game.

Using computational tools, a team of researchers at the University of Washington has designed and built from scratch a molecule that, when confronted with a coronavirus in the lab, can attack and isolate it at least as well as an antibody. When spraying the noses of mice and hamsters, it also seems to protect animals from serious disease.

This molecule, called a mini-binder because of its ability to attach to the coronavirus, is small and stable enough to be mass-delivered in lyophilized form. Bacteria can also be designed to dispose of these mini-binders, potentially making them not only effective but also cheap and convenient.

The team’s product is still at a very early stage of development and will not be on the market any time soon. But for now, “it looks very promising,” said Lauren Carter, one of the researchers behind the project, led by biochemist David Baker. Eventually, healthy people could self-administer the mini-binders as a nasal spray and possibly retain the incoming coronavirus particles.

“The most elegant application can be something you keep on the nightstand,” said Dr. Carter. “It’s a dream.”

Mini-binders are not antibodies, but they prevent the virus in similar ways. The coronavirus enters a cell using a kind of interaction between the locks and the keys, placing a protein called the spike – the key, in a molecular lock called ACE-2, which decorates the outside of certain human cells. Antibodies made by the human immune system can interfere with this process.

Many scientists hope that mass-produced imitators of these antibodies may help treat people with Covid-19 or prevent them from becoming ill after infection. But many antibodies are needed to control the coronavirus, especially if there is an ongoing infection. Antibodies also burden human production and delivery.

To develop a less sophisticated alternative, members of Baker’s lab, led by biochemist Longxing Cao, used a computational approach. Researchers are modeling how millions of hypothetical, laboratory-designed proteins will interact with the spike. After consistently eradicating the bad performers, the team selected the best among the group and synthesized them in the laboratory. They spent weeks switching between the computer and the bench, thinking of designs that matched the simulation and reality as accurately as possible.

The result is a completely homemade mini-binder that easily sticks to the virus, the Science team said 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 study. If adapted for other purposes, Dr. Williams added, “it would be a big benefit for bioinformatics. “

The team is now working on in-depth training algorithms that could teach lab computers to streamline the iterative process of trial and error in protein design, giving products for weeks instead of months, Dr. Baker said.

The novelty of the mini-binder approach can also be a drawback. For example, the coronavirus may mutate and become resistant to the do-it-yourself molecule.

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

His team has also designed a protein that can stop the virus from invading cells, but their DIY molecule is a little better known. This is a smaller, healthier version of the human protein ACE-2 – one that has far stronger adhesion to the virus, so the molecule could potentially serve as a lure that lures the pathogen away from vulnerable cells.

The development of resistance would be useless, said Christopher Barnes, a structural biologist at the California Institute of Technology who is partnering with Neolekin on their project. A coronavirus strain that can no longer be tied to bait is also likely to lose its ability to bind to the real thing, the human version of ACE-2. “It’s a big fitness price for the virus,” Dr. Barnes said.

Mini-binders and ACE-2 lures are easy to make and are likely to cost only pennies a dollar compared to synthetic antibodies, which can carry price tags for the high thousands of dollars, Dr. Carter said. And while antibodies need to be kept cold to maintain longevity, DIY proteins can be designed to perform well at room temperature or even in more extreme conditions. The University of Washington’s mini-binder “can boil and is still fine,” Dr. Cao said.

This endurance 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 ongoing infection.

The two design molecules also engage the virus in extremely strong compression, allowing less to do more. “If you have something that connects this well, you don’t have to use that much,” said Atabey Rodriguez Benitez, a biochemist at the University of Michigan who was not involved in the study. “That means you get more money for your money.”

Both research groups are researching their products as potential tools not only to fight infection but also to prevent it directly, somewhat as a short-term vaccine. In a series of experiments described in their article, the Neoleukin team obscured its ACE-2 bait in the noses of hamsters and then exposed the animals to coronavirus. Untreated hamsters get dangerously ill, but hamsters who receive nasal spray do far better.

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

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

In the future, 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 as the pandemic rages. “It’s very complementary,” Dr. Carter said. If all goes well, molecules like these could join the growing arsenal of public health measures and drugs that already exist to fight the virus, she said: “This is another tool you could have.”

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