Polypeptide Carrier Extends the Effectiveness of Small Protein Drugs

Drug developers have used advanced genetic engineering techniques to combine small protein drugs with a large polypeptide carrier molecule so that the combination remains in the circulation for up to 60 times longer than the original drug.

A major problem in using small protein drugs such as interferon is the rapid clearing of the drug from the circulatory system. In the case of interferon, patients must receive high doses every other day in order to maintain an effective level in the blood.

Various methods have been applied to solving this problem, principally by attaching the drug to a large carrier molecule such as polyethylene glycol (PEG). PEG is a random coil long-chain polymer that swells by adsorbing water, eventually becoming too large to be filtered from the blood stream. Unfortunately, the polymer is not metabolized and can accumulate to toxic levels.

A new and promising approach has been developed by investigators from Technische Universitaet Muenchen (Munich, Germany). They have replaced PEG with a large polypeptide consisting of many repeats of the amino acids proline, alanine, and serine (PAS). The PAS polypeptide also swells in water, but in contrast to PEG, PAS is slowly broken down into fragments that are excreted by the body.

Biologic preparation of "PASylated" proteins is simpler than chemical preparation of "PEGylated" ones. DNA segments encoding the PAS amino acid sequence is attached to the sequence for a protein such as interferon. This modified DNA is then inserted into bacteria that produce the PASylated interferon in one piece.

Initial studies have indicated that PASyated interferon has a half-life in the blood that is prolonged by a factor of 60, which should allow a significant extension of dosing intervals during medicinal therapy.

The potential for the future market for PASylated protein drugs has led to the creation of a dedicated company called XL-Protein, GmbH (Munich, Germany), which will exploit the new technology.

"Our technology has the potential to give birth to a whole new generation of blockbuster medications," said Dr. Arne Skerra, professor of biological chemistry at Technische Universitaet Muenchen.

Related Links:
Technische Universitaet Muenchen
XL-Protein