13TSB_SynBio:Enhanced discovery and scalable synthesis of therapeutic cyclic peptides

Natural products often have very desirable biological and material properties. In the future there will be immense pressure to produce economically valuable materials with much reduced environmental impact. This means the Industrial Biotechnology sector (which is related to, but distinct from the Pharmaceutical Industry) in the UK has a golden opportunity to harness world class science. This proposal links first class academic science with unique expertise available in an innovative small company, Ingenza. The main aim of the project is to develop a bacterial system (cell factory) for the production of novel customizable and highly modified cyclic peptides in significant quantities. Cyclic peptides are found as antibiotics, anticancer agents, in hormone therapy and in immune system modifying agents. In addition to their direct medicinal role, they are also very useful tools in studying biological processes, this second role, as tools, is underdeveloped simply because natural products are hard to make in sufficient amounts. The proposed work will solve these problems by providing a plug 'n' play system in which changes can be made simply and quickly to the 'cell factory' to produce a vast array of cyclic peptides at a useful scale.

Cyanobactins are macrocyclic peptides that have underexploited potential in combating a range of diseases such as infection, inflammation, cancer and immune diseases. There is great interest from the pharma industry in their development as therapeutic agents but these compounds are extremely challenging to produce with existing methods, severely hampering their exploitation. We will overcome this limitation, using combinatorial synthetic biology and biobased parts, to design and build the necessary pathways in engineered microbes for scalable production of a broad range of macro-cyclic peptides. This collaboration combines academic groups with deep knowledge of cyanobactin biosynthesis, structural biology and protein chemistry with a leading UK based IB company with expertise necessary for the required synthetic biology approach. The project will deliver improved products and processes to create novel cyclic peptides with the potential to treat a range of diseases.

Who might benefit from this research? In terms of economic impact the main beneficiaries will be the UK Industrial Biotechnology sector. A direct link to an innovative UK biotechnology company, and a letter of support from a large pharmaceutical company (Astra Zeneca) are clear indications of this. Ingenza's investment shows that the biotechnology we are developing is of importance and utility to the UK industrial biotechnology sector. We see the technology as enabling new products with a range of applications in pharmaceuticals, biological research and even new materials. Society will benefit by the production of new pharmaceutical lead molecules for diseases which are hard to treat using small molecule therapeutics.

How might they benefit from this research? The Industrial Biotechnology sector will benefit from adopting new but de-risked technology. They will benefit from exchange of people and of ideas. The cell based process for the production of complex cyclic peptides will give rise to new materials which we will test for bioactivity in a number of disease targeted screens. We have extant screening collaborations with Merck in the US and academic groups in the UK and Europe. These compounds can then be developed for commercial application and can be licensed or co-developed by industry.

Cyclic peptides are now recognised to be particularly powerful molecules in modulating protein-protein interactions. There is an urgent need for such diverse arrays of complex molecules as small organic molecules that are the mainstay of the pharmaceutical industry are not proving effective in disrupting protein-protein interactions. Our approach will produce materials that can be modified easily and produced in a cell factory. The use of efficient biotransformation enzymes will reduce the use of chemical reagents, solvents, energy and waste products.