Cross-dressing Proteins - Isis Project No 3729

Oxford researchers have shown for the first time that a “cross metathesis” strategy can be used to manufacture protein-based drugs which are closer to natural human proteins.

Marketing Opportunity

Professor Ben Davis and co-workers have developed an alkene cross metathesis technique which can be used during drug development for the post-translational modification of proteins. The cross metathesis step occurs rapidly, selectively and in high yields under aqueous conditions.

Proteins have been successfully used as therapeutic drugs for the treatment of cancer, heart attacks, diabetes, anaemia and several other diseases. For proteins to be therapeutically effective, their structure and function must be manipulated to control the way that they are transported around the body, recognised by tissues, absorbed by cells and eventually metabolised. Typically, therapeutic proteins (e.g. erythropoietin, insulin) are produced using bacteria, yeast or mammalian cells. Cell systems attempt to mimic the way that proteins are produced in human cells. However, the different biochemistry of the host cell systems means that they do not modify the proteins in an identical way to human cells. There is a clear need for protein modification techniques that do not rely on host cell systems.

The Oxford Invention

A two step procedure has been developed (Fig 1). First, cysteine residues on a protein are modified, either via genetic or chemical methods, to install an allylsulphide group¹. Next, the allylsulphide group undergoes alkene cross metathesis in the presence of a Hoveyda-Grubbs 2^nd generation catalyst; a commercially-available catalyst; to generate a modified protein^2,3. This method provides an efficient means for the post-translational modification of proteins by carbon-carbon bond formation. This method has been employed successfully in the preparation of PEGylated-, farnesylated- and glycosylated proteins, which are relevant in the manufacture of synthetic vaccines and other protein-based drugs.

Figure 1

Patent Status

This technology is the subject of an international patent application, and Isis would like to talk to companies interested in developing the commercial opportunity that this represents. The technology is not available for use in the field of AIDS vaccines and their production.

References

¹ G.J.L. Bernardes, J.M. Chalker, J.C. Errey, B.G. Davis, J. Am. Chem. Soc., 130, 5052 (2008).
² Y.A. Lin, J.M. Chalker, N. Floyd, G.J.L Bernardes, B.G. Davis, J. Am. Chem. Soc., 130, 9642 (2008).
³ K. Kirshenbaum, P.S. Arora, Nat. Chem. Biol., 4, 529 (2008).

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