New strategy for protein modification - Isis Project No 3620

A new chemical method provides a mild, efficient and inexpensive route for the site-selective modification of proteins, which can be used to prepare therapeutic proteins.

Marketing Opportunity

Post-translational modification (PTM) is an important step in protein biosynthesis that increases the range of functions of a protein. Selective engineering of proteins using PTM has been used to develop therapeutic proteins for the treatment of cancer, cystic fibrosis, diabetes, anaemia, and more. The market for therapeutic proteins is large ($37 billion in 2003) and growing (>15% growth p.a.), and is expected to reach $90 billion by 2010.  However, the accurate and consistent bioprocessing of therapeutic proteins is very difficult, due to their sensitivity to preparative conditions. This presents challenges for the manufacture, regulation and safety of therapeutic proteins. There is an immediate need for methods that enable specific and controllable modification of proteins.

The Oxford Invention

Oxford researchers have developed a new method for the site-selective modification of proteins.1 In this method, cysteine, a sulphur-containing amino acid, is converted to dehydroalanine (Dha) via an oxidative elimination.  Dha provides a convenient chemical handle for further post-translational modifications, enabling selective attachment of other molecules (e.g. peptides, carbohydrates, lipids, phosphates) to proteins. Poly-peptides and glycoproteins, which have applications in synthetic vaccines, and oncological and hematological treatments, are just two examples of modified proteins that can be accessed using this method.  The reaction proceeds quickly and under mild conditions using a chemical promoter.  Importantly, the reaction is selective for cysteine over methionine, another sulphur-containing amino acid, and the protein structure is not affected other than at the cysteine modification target. The method is advantageous over other PTM methods because it produces one well-defined protein conjugate rather than an heterogenous mixture. The method is also simple, quick and relatively inexpensive compared to enzymatic techniques.

Ref 1. G.J.L. Bernardes, J.M. Chalker, J.C. Errey, B.G. Davis, J. Am. Chem. Soc, 130, 5052 (2008).

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. Please contact the Isis Project Manager to discuss this further.

Please refer to article in Nature Chemical Biology Reference: K. Kirshenbaum, P. S. Arora, NatChemBiol, 4, 529 (2008).
http://www.nature.com/nchembio/journal/v4/n9/pdf/nchembio0908-527.pdf

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