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

Lead Research Organisation: University of St Andrews
Department Name: Chemistry

Abstract

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.

Technical Summary

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.

Planned Impact

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.

Publications

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Houssen WE (2014) An efficient method for the in vitro production of azol(in)e-based cyclic peptides. in Angewandte Chemie (International ed. in English)

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Oueis E (2016) Enzymatic Macrocyclization of 1,2,3-Triazole Peptide Mimetics. in Angewandte Chemie (International ed. in English)

 
Description We have discovered a way to increase the chemical diversity of natural products in the patellamide class. This class of molecules has some very interesting medical properties including reversal of cancer drug resistance. In their current isolated form the molecules are not useful, we need to make variants of them. This project allowed us to make molecules that do not exist in nature.
Exploitation Route We are forming a company to exploit the intellectual property.
Sectors Healthcare,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology

 
Description In this completed project we successfully used intein technology to ligate synthetic peptides to leader peptides. This creates a new substrate peptide for the patellamide pathway. Of critical importance is that approach allows us to combine chemical diversity with enzymatic processing giving rise to new molecules.
First Year Of Impact 2014
Sector Healthcare,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology
Impact Types Economic

 
Description Primary school visit toHamilton 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact I spent a whole day with primary school children conducting science experiments. The initial focus was for children with special educational needs. The visit was carried at St John Primary School in Hamilton.
Year(s) Of Engagement Activity 2016
 
Description Schools visits 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact Each year I host visits to my lab from local secondary school (10's of pupils) and I also give a talk to visiting school pupils on science (approx 50 pupils).

Some of the children seemed to appreciate that chemistry was important in biology.
Year(s) Of Engagement Activity Pre-2006,2006,2007,2008,
 
Description Training and workshops 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Between 20 to 50 pupils per year visit St Andrews and as part of this, they are exposed to structural biology.

Teachers report increased enthusiasm for biomedical science
Year(s) Of Engagement Activity 2006,2007,2008,2009,2010
 
Description workshops 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Helped in the training of post-graduate students in structural biology at the following meetings.
CCP4/ZCAM workshop, Zaragoza, Spain March 2012
CCP4/ APS workshop, Argonne, USA, June 2012
CCP4/APS workshop, Argonne, USA, June 2013
CCP4/CeBEM workshop, Montevideo, Uruguay, April 2013

Widespread use of UK authored software.
Year(s) Of Engagement Activity 2013,2014
URL http://www.ccp4.ac.uk