Peptide Therapeutics

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Activotec has intellectual property for the modification and production of peptides for therapeutic use.

Activotec has developed intellectual property in the field of peptide engineering which allows many natural peptides to be stabilized against proteolytic digestion - a major route of catabolism for natural peptide hormones, and a major route of elimination of peptide and protein drugs - limiting their effectiveness. For example, GLP-1 is destroyed by a catabolic enzyme 'dipeptidyl peptidase IV' which cleaves off an essential N-terminal dipeptide moiety. This cleavage is the major route of elimination of GLP-1 in the body. Although the natural hormone GLP-1 has highly beneficial anti-diabetic effects (stimulating insulin secretion, and acting as a growth factor for beta cells) it transpires that, in its natural form, GLP-1 is so short lived as to be therapeutically useless (requiring continuous infusion to exert the beneficial effect).

In Activotec's technology, alterations are made to susceptible peptide bonds rendering peptides invulnerable to key proteases that would otherwise destroy them, thereby preserving the presence of the drug in the body. This engineering concept has been exemplified for GLP-1 - creating drug candidate molecules that are protected by a granted patent, and which have enhanced stability and longevity of action. Moreover, unlike Byetta, which is based on a reptilian sequence homologous to GLP-1, the engineered Activotec peptide exhibits the natural peptide sequence (with respect to all of its side chains and all-but-one of its peptide bonds), and is less liable to give rise to immune responses in recipients. Although immune responses to Byetta have not proven problematic (ie. Byetta is safe despite eliciting antibodies in some recipients), protein and peptide immunogenicity is difficult to predict and needs to be considered on a case-by-case basis, and generally one would wish to minimise immunogenicity of novel peptide drugs, by staying as close as possible to the natural peptide sequence. The Activotec peptide engineering technology allows this principle to be adhered to.

Activotec's novel peptide drugs are made by fragment condensation which is greatly facilitated by our expertise in reverse peptide synthesis - whereby the larger fragment is made by conventional solid phase methodology, and the smaller fragment by reverse synthesis - providing great flexibility in the ligation chemistries that may be used, allowing a variety of protease-resistant bonds to be rapidly created and explored for their pharmacological properties.

N- to C- Directed Solid-Phase Peptide Synthesis

Solid phase peptide synthesis from N-to-C direction was developed in the early nineties in Southampton, UK [Sharma, Patent WO 90/05738]. The alkoxysilyl moiety was used as a temporary carboxyl protecting group. Using this novel N-to-C methodology a number of peptides have been synthesised. This N to C method is disclosed in Sharma, R. P., Jones, D. A., Corina, D. L. and Akhtar, M. (1994) in Peptides: Chemistry, Structure and Biology, Proceedings of the Thirteenth American Peptide Symposium (Hodges, R. S. and Smith, J. A., eds.), pp. 127-129, ESCOM, Leiden, , Jones, D. A. (1993) PhD Thesis, University of Southampton.

The important advantage of this strategy is that it allows the preparation of peptide analogues possessing C-terminal modifications (such as esters, thioesters, alcohols and aldehydes) and peptides possessing peptide bond modifications (such as reduced peptide bonds, urea and isosteres) on the solid phase which has important applications in the synthesis of peptides of therapeutic interest e.g. a-MAPI [Sharma, Chem. Commun., 1998, 1449-1450]

Research and development

First efficient synthesis of a-MAPI (download the article as a PDF file)

The methodology has been extensively scrutinized for any racemisation produced during peptide synthesis on the solid-phase by using both physical (specific optical rotation, RP-HPLC analysis) and chemical (enzymatic studies) methods. No detectable racemisation has been observed for the synthesis of peptides during N-to-C synthesis. The method is simple, mild and amenable to automation [Anja Johansson J. Comb. Chem. 2000, 2, 496-507]


Intellectual Property

Activotec has filed a number of patent applications based on the above technology. Further patents have been filed relating to the development of novel peptide-based products for the treatment of diabetes.

For further information please contact Chris Littlewood on +44 1223 260008 or use our enquiry form