Molecular origami: Protein engineering emerges to fight disease

SEATTLE – Aaron protein engineer Chevalier has a hunch that origami – on a smaller scale – could be the future of drug design.

So he and a team here at the University of Washington spend the day intricate design folded chains of amino acids to create molecules that do not exist in nature. The goal: Create a protein that can bind to a virus such as flu and prevent it from infecting cells. Or one that could break the gluten, effectively taming gluten allergies.

“You could imagine a future in which we are able to design an essentially unlimited number of new proteins that are basically the drugs of the future, vaccines of the future,” said David Baker, a biochemist who leads Institute university to design proteins.

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Naturally, warnings abound.

On the one hand, it is not clear whether our immune system will accept new proteins that have never seen before. They could cause new allergies. The body could reject them. Or they could be not work in real life, even if they look good on a computer screen. And in practical terms, it is likely to be years before any of these new design proteins make their way to our medicine cabinets.

“As with any medication, you should always test experimentally before you stick in a person,” Baker said.

proteins Yang Zhang, a professor of biological chemistry at the University of Michigan, is also engineering. He said Baker’s work is promising, but a theoretical turning into a functional protein therapeutic will take time because the protein effectively will be interacting with an entire system, not just the intended objective.

“It is a very complicated for a drug process. It is necessary to consider not only these interactions, it is also necessary to take into account the side effects or interaction with the environment, and many other avenues of proteins “, He said.

In a summer afternoon, Chevalier demonstrated the principle of the protein folding a group of students visiting the laboratory to fold and unfold a cup of origami. That is difficult, he said. But the design of a new molecule to combat the disease is even more difficult.

“It is not just figuring out the folding of a cup. It’s like if you want the cup is rigid or hold a lot of water, or it has to last long,” Chevalier said.

proteins are the workhorses of the human body; there are millions out there that are approved by the evolution in progress, our bodies with a precision of Swiss watches. Protein engineering is about design that allows them to work together in new ways to combat the disease, said Don Hilvert, a professor of organic chemistry at the ETH Zurich in Switzerland, working with Baker.

In the past, scientists used their knowledge of thermodynamics and biochemistry, with a dash of intuition and trial and error, to find possible therapies. Now, Baker’s team can ask a software program to reach a protein that is a certain size and shape, have a certain chemistry and will perform in a certain way. And its software, Rosetta will give you dozens of candidates who can build and test.

Informatics all combinations

Halfway computer lab IPD, engineers protein in the hunch shirts monitors, examination of designs and improvements coding Rosetta. The software analyzes dozens of combinations of amino acids to find those that meet the specified size, shape and chemical parameters -. And it would be possible to build, which means they do not defy the laws of physics

“It is literally a computer fantasy,” said Neil King, a researcher IPD.

Rosetta can reach a lot of fast molecules. When Baker and colleagues published an article in Science in July on one of his designs – a “molecular cage” that would help deliver drugs – not published a single plane. They published 10 versions. They are pretty sure that nothing exists in nature.

Once Rosetta protein design is performed, scientists try. Order the necessary DNA sequence online and then pop into bacteria or yeast that will use these genetic instructions to build a new protein.

Chevalier protein antibody-based designs that he thinks will fight the best blocking flu virus out of our cells. Rosetta structures gave candidates. His next challenge is showing his designs will work.

“If one thinks of antibodies, which evolved to be circulating in the bloodstream,” he said. “They are not necessarily evolved to be packed and stored without the need for refrigeration. They are not designed to be produced on a large scale, to be soluble, to be able to concentrate.”

expects Chevalier, from scratch, you can make a single protein with all these features -. Which could, in theory, become the basis for a low cost, drugs nonperishable

Although it has not yet succeeded, Chevalier has proved a highly stable protein in mice. That protein flu stopped as reported in an article published this February . The laboratory work is funded mostly by government and nonprofit agencies, but they do have funds Takeda Pharmaceuticals. Now Chevalier and Baker are launching a biotechnology company called Virvio for further development.

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