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Beta-proteins better than Nature's choice?

By Mike Nagle , 14-Feb-2007

Scientists have shown it is possible to mimic the complex stable structure of natural proteins using a different type of amino acid building block, potentially opening the door to more effective, longer-lasting biologic drugs.

A US group of researchers headed by Yale professor Alanna Schepartz, have attached a string of beta-amino acids together that self-assemble into a structure similar to a natural protein. The Zwit1-F beta-peptide they made was then analysed using X-ray crystallography to determine its structure.

Since these beta molecules have protein-like structures, in the future, scientists could potentially make beta equivalents of biopharma drugs. These could act like their natural alpha-protein counterparts but without being degraded by the body or recognised by the immune system.

There are currently more than 300 biopharma drugs in late-stage clinical trials targeting more than 200 diseases, and a global estimated to be $50bn (€38.2bn) in 2005 with growth rates almost double that of the pharma industry in general. Biopharmaceuticals are not without their problems though.

Generally, protein-based are rapidly degraded in the body, leading to frequent doses being needed. A further inconvenience is the fact that often the therapy must be given by injection and this only leads to further patient compliance problems. Beta-proteins have the potential to solve all these problems.

Although the sidechain of each amino acid is different, their backbone remains the same and enables them to attach together into a chain. Beta-amino acids are different to alpha-amino acids because there is an extra methylene (CH2) group on their backbone.

"When you look at the beta bundle from afar, it looks exactly like an alpha-protein," Prof Schepartz explained to DrugResearcher.com.

"The X-ray structure featured in the report shows a molecule that shares many of the structural characteristics of natural proteins and related studies show that the physical properties of the molecule are also remarkably similar to natural proteins," she explained.

One of these studies looked at the number of water molecules found in the crystals. Proteins typically have a core that locks out water molecules and so generally have less water in their crystals than those containing small molecules. Prof Schepartz explained that her team found this so-called Matthew's coefficient was in the right range for a protein.

The structure is also fairly robust. Prof Schepartz's team has seen that substituting amino acids found on the surface of the beta bundle doesn't affect its overall structure.

"The differences only become apparent when you look much closer," she continued.

Protein structure can be thought of on three levels. The amino-acid sequence is its primary structure. This chain can fold into secondary structures such as spiral-shaped helices. If several of these helices are attached together, they can interact with each other to form a stable tertiary structure.

Prof Schepartz found that the the beta-helices bunch together more closely than in normal proteins. This is because the extra part of their backbone leads to their sidechains sticking out at different intervals on the spiral, enabling two helices to interlock together rather than interact through the tips of their sidechains, as is the case with alpha-helices.

The Yale team is now focusing on generating other beta-peptides, only this time using a natural sequence with a known function. The future possibility of designing beta-based biologics rests on scientists being able to replicate specific proteins related to disease.

Beta-proteins could also be less expensive to produce and more stable on the shelf than alpha-protein drugs, explained Prof Schepartz.

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