Good antibody. Are Machine Made Molecules Better?

Coronaviruses may be new, but nature long ago gave humans the tools to recognize them, at least on a microscopic scale: antibodies, latching on pathogens and allowing them to invade cells. Y-shaped immune protein that can block.

Millions of years of evolution have refined these proteins into weapons to combat today’s diseases. But in just a few months, a combination of human and mechanical intelligence could have defeated Mother Nature in her own game.

A team of researchers at the University of Washington used computational tools to design and build a molecule from scratch that could attack and isolate at least as much as an antibody when fighting a coronavirus in the laboratory. Stimulating the nose of mice and hamsters also seems to prevent animals from becoming seriously ill.

This molecule is called a mini-binder because of its ability to aggregate in coronavirus, and it is small, stable, and can be shipped together in a lyophilized state. Bacteria can also be designed to unleash these mini-binders, which can be not only effective, but also cheap and convenient.

The team’s products are still in the very early stages of development and will not be on the market soon. But so far, “looks very promising,” said Lauren Carter, one of the researchers behind the project led by biochemist David Baker. Ultimately, healthy people may be able to self-administer minibinders as nasal drops, potentially repelling inbound coronavirus particles.

“The most elegant application may be to leave it on the bedside table,” Dr. Carter said. “It’s a kind of dream.”

Minibinders are not antibodies, but they block the virus in much the same way. Coronavirus uses a type of lock-and-key interaction to enter cells and adapt a protein (key) called spikes to a molecular lock called ACE-2. ACE-2 decorates the outside of certain human cells. Antibodies produced by the human immune system can interfere with this process.

Many scientists hope that mass-produced mimics of these antibodies will help treat people with Covid-19 and prevent them from getting sick after being infected. However, many antibodies are needed to control the coronavirus, especially if the infection is ongoing. Antibodies are also cumbersome to produce and deliver to people.

To develop a grumpy alternative, members of the Baker Lab, led by biochemist Longxing Cao, adopted a computational approach. Researchers have modeled how millions of lab-designed virtual proteins interact with spikes. The team removed the poorest ones in order, then selected the best ones and synthesized them in the lab. They spent weeks switching between computers and benches, tweaking the design to match the simulation and reality as closely as possible.

As a result, a completely homemade mini-binder easily adhered to the virus, the team reported in science last month.

“It’s not just about building natural proteins,” said Usher Williams, a chemistry engineer at Cornell University who wasn’t involved in the study. When adapted for other purposes, Dr. Williams added: For bioinformatics. “

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

However, the novelty of the mini-binder approach can also be a drawback. For example, a coronavirus can mutate and become resistant to DIY molecules.

Daniel Adriano Silva, a biochemist at Seattle-based biopharmacy company Neoleukin and previously trained with Dr. Baker at the University of Washington, may have come up with another strategy to solve the tolerance problem.

His team has also designed proteins that can prevent the virus from entering cells, but their DIY molecules are a little more familiar. This is a smaller, more robust version of the human protein ACE-2, which grips the virus much more strongly, allowing this molecule to act as a decoy that pulls pathogens away from vulnerable cells.

Christopher Barnes, a structural biologist at the California Institute of Technology and partner with Neoroykin on the project, said it was useless to develop resistance. Coronavirus strains that can no longer bind to decoys will probably lose their ability to bind to the genuine human version of ACE-2. “It’s a big fitness cost for the virus,” said Dr. Burns.

According to Dr. Carter, both mini binders and ACE-2 decoys are easy to make and can cost as little as $ 1 compared to synthetic antibodies that can be priced in the thousands of dollars. .. Antibodies need to be kept cold to extend their lifespan, but DIY proteins can be designed to work well at room temperature or even in more extreme conditions. The University of Washington mini-binder “can be boiled and is still okay,” said Dr. Cao.

Its durability makes these molecules easier to transport and easier to administer in a variety of ways. Probably by injecting into the bloodstream as a treatment for an ongoing infection.

Both designer molecules involve the virus very tightly and can do more with less. “If there’s something that connects this well, you don’t have to use that much,” said Attabey Rodríguez Benítez, a biochemist at the University of Michigan who wasn’t involved in the study. “It means you are getting more value for your money.”

Both research groups are looking for their products as potential tools not only to combat infection, but to completely prevent infection, such as short-lived vaccines. In a series of experiments described in their paper, the Neoroykin team sprayed ACE-2 decoys on hamster noses and exposed animals to coronavirus. Untreated hamsters became dangerously ill, but hamsters given nasal drops worked much better.

Dr. Carter and her colleagues are currently conducting similar experiments with minibinders with similar results.

Researchers warned that these findings may not be translated into humans. And neither team has yet devised the perfect way to administer the product to animals or humans.

In the future, there may still be opportunities for the two designer proteins to work together. As the pandemic intensifies, at least in the same war, if not the same product. “It’s very complementary,” said Dr. Carter. If all goes well, molecules like these could join the increasing arsenal of public health measures and drugs already in place to fight the virus, she said: “This is Another tool you can have. “

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Good antibody. Are Machine Made Molecules Better?

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