Synthetic proteins better than real ones?

Synthetic proteins better than real ones?

Summary: Researchers at the Howard Hughes Medical Institute (HHMI) and Yale University have built proteins which don't exist in the natural world. They've constructed these proteins from beta-amino acids, which are distinct from the alpha-amino acids that compose natural proteins. Their synthetic proteins are as stable as natural ones, but provide a distinct advantage. As they will not be degraded by enzymes or targeted by the immune system as natural ones are, these beta-peptides could be used as the basis for future drugs that would be more effective than natural protein drugs. Still, a question remains: why don't these proteins exist naturally? In other words, will drugs based on these man-made proteins be more efficient or more dangerous? Time will tell.

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Researchers at the Howard Hughes Medical Institute (HHMI) and Yale University have built proteins which don't exist in the natural world. They've constructed these proteins from beta-amino acids, which are distinct from the alpha-amino acids that compose natural proteins. Their synthetic proteins are as stable as natural ones, but provide a distinct advantage. As they will not be degraded by enzymes or targeted by the immune system as natural ones are, these beta-peptides could be used as the basis for future drugs that would be more effective than natural protein drugs. Still, a question remains: why don't these proteins exist naturally? In other words, will drugs based on these man-made proteins be more efficient or more dangerous? Time will tell.

These findings have been made by Alanna Schepartz, professor of chemistry at HHMI and Yale University (read her bio here or there), and her students and colleagues in her Laboratory of Chemical Biology. Below is a description of their research project.

In their studies, Schepartz and colleagues synthesized a β-peptide they called Zwit1-F. They allowed the chain of β-amino acids to assemble into its own structure and then analyzed it with x-ray crystallography, a technique in which x-rays are directed through a crystal of a protein so that its structure can be deduced from the resulting diffraction pattern.
The researchers found that the Zwit1-F peptide folded into a bundle of coiled helices that resembled those in natural proteins. In particular, Schepartz noted that both natural proteins and the β-peptide bundle folded in ways that placed the "water-hating" hydrophobic segments of the molecule in the core of the structure. Other features, too, were remarkably similar to a coiled helix bundle formed of β-amino acids.

The illustration below shows "ribbon diagram representations of a beta-peptide bundle illustrating packing between helices (left) and within the hydrophobic (green) core (right)" (Credit: Credit: Douglas S. Daniels of Alanna Schepartz's lab)

The 'Beta-peptide bundles

But why these proteins don't exist in our world?

"Certain β-amino acids are naturally synthesized in cells, and they are even loaded onto transfer RNA molecules that carry the amino acid components to the protein-making machinery of the cell, the ribosome," she noted. "But to my knowledge, there are no ribosomally constructed proteins that contain β-amino acids," said Schepartz.

So the researchers don't have a clear explanation for the non-existence of such proteins in real life, but that doesn't prevent them to think about future usages in medicine. I hope that their future work will be closely scrutinized.

For more information about these findings, you can read a Yale University news release, "Yale Chemists Show that Nature Could have Used Different Protein Building Blocks" (February 5, 2007), from which the above image has been picked, or an article from Chemistry World, "Protein's non-natural alternative" (February 7, 2007).

Finally, this research work has been published by the Journal of the American Chemical Society under the name "High-Resolution Structure of a β-Peptide Bundle" (Volume 129, Number 6, Pages 1532-1533, February 14, 2007). Here are two links to the abstract and to the full paper (PDF format, 2 pages, 163 KB).

Sources: Howard Hughes Medical Institute news release, February 5, 2007; and various other websites

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