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Antibodies are good. Are 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 cling to agents 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 the space of a few months, a combination of human and machine intelligence may have beaten Mother Nature at her own game.

Using computer tools, a team of researchers at the University of Washington designed and built from scratch a molecule that, when opposed to coronavirus in the laboratory, can attack and at least sequester it as well as an antibody. When sprayed on the noses of mice and hamsters, it also appears to protect animals from serious disease.

This molecule, called a mini-binder for its ability to glomize on the coronavirus, is small and stable enough to be shipped en masse in a lyophilized state. Bacteria can also be engineered to produce these mini-binders, making them potentially not only effective, but also cheap and convenient.

The team’s product is still in the very early stages of development and won’t hit the market anytime soon. But so far, “it looks very promising,” said Lauren Carter, one of the researchers behind the project, who is led by biochemist David Baker. Eventually, healthy people might be able to self-administer the mini-binders in nasal spray form, and potentially keep incoming coronavirus particles at bay.

“The sleekest app could be something you keep on your nightstand,” Dr. Carter said. “It’s a bit of a dream.”

Mini-binders are not antibodies, but they counteract the virus in broadly similar ways. The coronavirus enters a cell using a kind of lock-key interaction, adjusting a protein called a tip – the key – into a molecular lock called ACE-2, which adorns the exterior of some human cells. Antibodies made by the human immune system can interfere with this process.

Many scientists are hoping that the mass-produced imitations of these antibodies could help treat people with Covid-19 or prevent them from getting sick after being infected. But a lot of antibodies are needed to contain the coronavirus, especially if an infection is in progress. Antibodies are also expensive to produce and deliver to people.

To develop a less capricious 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 would interact with the peak. After sequentially eliminating the bad results, the team selected the best from the group and synthesized them in the lab. They spent weeks switching between the computer and the bench, tinkering with designs to match simulation and reality as closely as possible.

The result was a completely homemade mini binder that easily adhered to the virus, the team reported in Science last month.

“It’s more than just building natural proteins,” said Asher Williams, a chemical engineer at Cornell University who was not involved in the research. If adapted for other purposes, Dr Williams added, “it would be a big win for bioinformatics.”

The team are now playing around with deep learning algorithms that could teach lab computers to streamline the iterative process of trial and error designing proteins, yielding products in weeks instead of months, said Dr Baker.

But the novelty of the mini-binder approach could also be a downside. It is possible, for example, for the coronavirus to 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 come up with another strategy that could solve the resistance problem.

His team also designed a protein that can prevent the virus from invading cells, but their DIY molecule is a little more familiar. This is a smaller, more robust version of the human ACE-2 protein – a protein that has a much stronger hold on the virus, so the molecule could potentially act as a decoy that keeps the pathogen away from cells. vulnerable.

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

The ACE-2 mini-binders and decoys are both easy to make and will likely cost only pennies on the dollar compared to synthetic antibodies, which can carry prices in the thousands of dollars, Dr. Carter said. And while antibodies need to be kept cold to preserve longevity, DIY proteins can be designed to work very well at room temperature or in even more extreme conditions. The University of Washington mini-binder “can be boiled and it’s always OK,” Dr. Cao said.

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

The two design molecules also both engage the virus in extremely tight pressure, allowing less to do more. “If you have something that ties that together 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. “It means you get more for your money.”

The two research groups are exploring their products as potential tools not only to fight infection but also to prevent it outright, much like a short-lived vaccine. In a series of experiments described in their article, Neoleukin’s team misted their ACE-2 decoy into hamsters’ noses, then exposed the animals to the coronavirus. The untreated hamsters got dangerously ill, but the hamsters that received the nasal spray fared much better.

Dr Carter and his colleagues are currently running similar experiments with their mini-workbook 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 administer their products to animals or humans.

The bottom line is, there may still be opportunities for the two types of design proteins to work together – if not in the same product, at least in the same war, as the pandemic rages on. “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 already in place to fight the virus, she said, “It’s another tool that you could have.”

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