Biotech R & D
- R & D Overview
- Inhibition of Secretion
- Creating Novel Proteins
- Therapeutic Potential
CREATING NOVEL PROTEINS
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Creating Syntaxin's Novel Proteins
The clostridial neurotoxins all share a common structure that consists of two peptide chains covalently linked by a disulphide bridge (see below).
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The larger of these chains, known as the heavy chain, contains two distinct structural domains: a recognition domain (HC) and a translocation domain (HN). Through binding to receptors on the surface of peripheral cholinergic neurons the recognition domain determines the neuronal specificity of the toxin, whilst the translocation domain enables the protein to enter the neuron. The smaller chain, known as the light chain (LC), is the catalytic domain that cleaves the SNARE proteins and so inhibits the fusion of the synaptic vesicles to the presynaptic membrane. Syntaxin's novel recombinant proteins consist of the HN and LC domains of a clostridial neurotoxin and a selected binding ligand to direct the protein to the chosen target cell. The proteins are further tailored through the selection of which clostridial neurotoxin is used as the backbone of the protein. This choice determines which member of the SNARE family is cleaved, and is critical as different cell types contain different SNARE protein isoforms.
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Clostridial neurotoxins are expressed as single polypeptide gene products that are activated post-translationally by proteolytic cleavage to generate the di-chain toxin protein.
Syntaxin produces its proteins from novel, synthetic genes that encode the desired recombinant protein incorporating both the clostridial toxin domains and the binding domain. Also encoded is a specific proteolytic activation sequence enabling post-expression activation of the product to a di-chain protein analogous to the clostridial neurotoxins. An important aspect of the Syntaxin technology is that the recombinant genes encoding our products are synthesised using a codon usage suitable for E.coli expression. Thus unlike clostridial neurotoxin genes, Syntaxin's recombinant genes can be efficiently expressed using standard E. coli expression systems. Using this approach Syntaxin has created a large number of novel recombinant proteins able to deliver the clostridial protease activity to different target cells (see above).