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Protein Drugs with More Power

Scientists are learning to control a class of proteins that could have greater staying power in the body.
February 23, 2007

Yale University researchers have taken a step toward controlling the structure of an unusual class of proteins called beta-peptides. Eventually, these peptides could become the basis for drugs that are cheaper to manufacture than existing protein-based pharmaceuticals and last longer in the body.

Protein puzzle: A representation of the 3-D structure of a novel peptide made by researchers at Yale University.

“Protein drugs are expensive to make, and they have a short lifetime on the shelf and in the body,” says Alanna Schepartz, a professor of chemistry at Yale. Most protein drugs in use and in development, such as antibodies that target cancer cells, are made from alpha-amino acids, which are the building blocks of naturally occurring proteins. But metabolic processes in the body’s cells also produce strands of beta-amino acids, which differ from alphas in that they have one extra carbon atom. These beta-peptides are metabolized much more slowly than alpha-proteins.

Before researchers can make beta-peptides into drugs, however, they must be able to control their three-dimensional structure. Researchers have been working on this problem for about a decade, says William DeGrado, professor of biochemistry and biophysics at the University of Pennsylvania. A protein’s function is to a large degree dependent on its structure; for example, some have pockets that fit another molecule the way a lock fits a key. “This is the first time people have made a [beta-peptide] and shown it folds into a 3-D structure with a proteinlike interior,” says DeGrado.

Previous researchers hadn’t been able to keep beta-peptides from clumping together, but Schepartz’s group was able to make discrete, self-assembling “bundles” of the peptides. These bundle structures are similar to the structure of proteins made by the body. “This is a very exciting step forward toward being able to make foldable, functional molecules,” says Kenneth Dill, professor of biophysics at the University of California, San Francisco.

Beta-peptides can probably do all the same things as the proteins the body normally makes, says Dill. But if researchers are able to reliably manufacture them, beta-peptides could have advantages over conventional protein-based drugs. Strings of alpha-amino acids must be relatively long before they can fold into a three-dimensional structure, but strings of beta-amino acids are able to do so at shorter lengths. Thus, these peptides could be less expensive to manufacture; as Schepartz says, they can “encode function in a smaller package” and therefore would require less starting material.

Another advantage stems from the slower breakdown of beta-peptides in the body. Protein drugs made of alpha-amino acids are easily recognized by the body and metabolized quickly–sometimes too quickly to perform their function. They also cannot be taken orally, because enzymes in the stomach would degrade them. Beta-peptides aren’t readily recognized by the body’s enzymes, so drugs based on them would last longer and could probably be taken orally.

The next step for the Yale chemists is to make functional beta-peptides. Having shown that beta-peptides can form structures as complex as those formed by alpha-peptides, they must demonstrate that the novel peptides can perform the same complex activities.

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