Manchester Chemical Biology Network

Lead Research Organisation: University of Manchester
Department Name: Chemistry

Abstract

Chemical biology is the area of science at the interface between chemistry and biology, which uses chemical tools including structural, physical and analytical methodologies as well as synthetic small molecules to gain deeper insight into the function and properties of biomolecules and biomolecular systems (cells). Whilst great benefit can be derived from such interdisciplinary research, particularly in the area of healthcare, boundaries that exist between traditional disciplines have hindered the progress of chemical biology in the UK. In 2006, the University of Manchester took the lead in addressing this issue by establishing the Manchester Interdiscplinary Biocentre (MIB), which was the first major university institute in the UK to bring chemists and biologists together to do research in the same building (ca. 300 in total). We propose to build on this solid foundation, using MIB as a focal point and meeting place, to develop a much wider chemical biology network that unites scientists from across the university including researchers in medical science who can further develop research in chemical biology for medical applications. Importantly, the new Manchester Chemical Biology Network (MCBN) will include partners and collaborators from the pharmaceutical and biotechnology industry, knowledge transfer networks, healthcare providers and medical charities. These end users of chemical biology will help guide the direction of the research in the network and enable us to establish critical cross-discplinary collaborations. Increasing the effectiveness of our collaborations with the end users will be essential if we are to see maximum benefit derived from this research. Ultimately this could include new approaches for the treatment of human disease ranging from bacterial infections through to cancer.

To enable maximum impact from our research to be realised, the network will focus on several key themes. The first theme, small molecules and chemical tools, will involve the development and application computational based approaches for drug design and virtual screening. Such activities can help identify potential drug candidates, which we will synthesise. Also many pharmacologically active small molecules are derived from natural sources (plants, soil bacteria and marine organisms). We will produce and modify these natural product leads using synthetic and biosynthetic methods. In the second theme, new concepts in target modulation will be developed including array based technologies for screening potential drug targets, where targets (proteins or oligosaccharides etc.) are attached to surfaces allowing high throughput imaging of their interactions with other cellular molecules including drugs. Crystallography and NMR methods, developed in Manchester, along with other physical methods will be applied to probe the structure and dynamics of cellular targets, which can further help in the design and optimisation of lead molecules for therapeutic applications. We will apply our knowledge of enzymology (how enzymes work) and cell biology (how the complex components of human cells interact) to uncover new enzymes, other biomolecular targets and pathways for therapeutic intervention, which we will interrogate with our arsenal of small molecules etc. In the third theme, target deconvolution, we will take a systems biology approach, which models all the components in the cell and allows the broader response of cells to abiotic substances (e.g. drugs) to be interpreted. This can be particularly important for predicting possible toxic (side) effects of drugs. In the final theme, intersection of large and small molecules, we will develop new methods for improving the properties of proteins and antibodies for use as therapeutic agents (biopharmaceuticals). We will also develop new drug delivery systems using nanoparticles and other smart materials programmed to target and release drugs in specific diseased cells, but not healthy cells.

Planned Impact

The MCBN will establish a unique platform to explore advances in chemical biology and their potential application across the biological and medical sciences. In addition, it will allow the development of innovative approaches to biological problems, provide a forum for exchange of best practice and expertise and allow collaborations to form solid sustainable links towards translational research with accelerated impact. Indeed, it is vital that translation of fundamental advances in chemical biology through to cell biologists, pharmacists and medics is possible to enable better drug design, identification of drug targets, optimisation of small molecule drug candidates through to biopharmaceuticals, and thus impact on human health. Whilst the healthcare grand challenge will be the main impetus for our research, some of the basic methodologies and technologies we develop could also be applied in the animal healthcare and agrochemicals area.

In addition to the obvious benefits to the academic community within the University of Manchester, nationally and internationally, the network will work closely with its industrial members to ensure knowledge transfer and commercial exploitation. This close industrial relationship of the network with companies from across the field including large pharmaceutical companies may impact on not only the nation's health, but also could contribute to wealth creation and economic competitiveness in the UK. The network will form a very strong cross disciplinary body that with its communication with non-government and government organisations will be in a position to influence scientific policy and reach out across the wider community through public engagement.

The network will form a strong basis for further collaborations and provide a unique opportunity to seed fund exchanges of expertise and personnel, explore proof of concept research and gather preliminary data. As such the full impact of the network may not be realised during the initial two year funding but will develop through stronger collaborations and development of full research projects. Results from collaborative projects will result in joint research publications in high quality peer-reviewed journals and will be presented at local, national and international conferences where appropriate. Exploitation of findings will be further enhanced by seeking follow-on funding to develop proof of principle, or biological application, in order to develop expertise to answer specific biological/medical problems.

The network will be expected to contribute significantly to the field of chemical biology and encourage an ethos of cross-disciplinary research. In addition to scientific advances, the network will spread an ethos of cross disciplinary networking and provide an unique opportunity for our research community to gain a better understanding of the industrial sector vital for development of transferable skills and their personal and professional training and development.

Publications

10 25 50
 
Description We have reported previously to EPSRC at the end of the grant.
Exploitation Route We have reported previously to EPSRC at the end of the grant.
Sectors Pharmaceuticals and Medical Biotechnology

 
Description Exploring natural product assembly line genomics and synthetic biology for discovery and optimisation of novel agrochemicals.
Amount £3,552,007 (GBP)
Funding ID BB/K002341/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 08/2013 
End 07/2018
 
Description MRC Concept in confidence award Tabernero
Amount £87,000 (GBP)
Organisation Medical Research Council (MRC) 
Department MRC Confidence in Concept Scheme
Sector Academic/University
Country United Kingdom
Start 05/2014 
End 06/2015
 
Description Rapid evolution of enzymes and synthetic microorganisms for the development of industrial biocatalysis.
Amount £3,604,502 (GBP)
Funding ID BB/K00199X/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 12/2012 
End 11/2017
 
Description Single cell metabolic profiling
Amount £451,142 (GBP)
Funding ID BB/K011170/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 08/2013 
End 07/2016
 
Description Sparking Impact Award Tabernero
Amount £11,900 (GBP)
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 01/2014 
End 09/2014
 
Description Understanding how aggregation influences the immune response to recombinant protein therapeutic drugs
Amount £459,000 (GBP)
Funding ID BB/L006391/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 06/2014 
End 06/2017
 
Description Alkyltransferases for selective alkynation of Rapalogs 
Organisation Biotica Technology
Country United Kingdom 
Sector Private 
PI Contribution This MCBN funded research collaboration brought together the research groups of Jason Micklefield and Barrie Wilkinson from Biotica and its new company Isomerase Therapeutics. This work explores mew methods for producing analogs of the immunosuppressive agent rapamycin.
Start Year 2011
 
Description Determination of waters contribution to protein-ligand binding 
Organisation Evotec
Country Germany 
Sector Private 
PI Contribution The MCBN provided collaborative pump prime funding to Richard Henchman to initiate collaborative discussions with Evotec. The 3 week visit has resulted in ongoing research collaborations between UoM, Evotec and the University of Edinburgh.
Start Year 2012
 
Description Development of protocols for protein structure analysis from IR spectra. 
Organisation Intertek
Country United Kingdom 
Sector Private 
PI Contribution This new collaboration between Intertek and UoM was seed funded through the MCBN to develop an accurate tool for analysing protein structure rapidly and with high accuracy.
Start Year 2011
 
Description Exciplex-based nanoparticles for potential biomedical and clinical applications. 
Organisation Link Technologies
Country United States 
Sector Private 
PI Contribution The MCBN facilitated collaborations between Elena Bichenkova?s research group and Link Technologies through funding of a pilot project to promote further development of the exciplex-based bio-molecular probes for potential applications in molecular diagnostics. The second aspect of the project explored novel uni-molecular exci-probes (supplied by Link Tech). The preliminary data will be used towards further development of these tools through additional funding and potential commercialisation. Tool development preliminary data obtained towards future collaborative research proejcts. This pilot project supported by MCBN has facilitated our collaborations with Link Technologies Ltd to promote further development of the exciplex-based bio-molecular probes for potential applications in molecular diagnostics.
Start Year 2011
 
Description Heparanase expression in insect cells, purification and crystallisation. 
Organisation Imperial College London
Country United Kingdom 
Sector Academic/University 
PI Contribution MCBN pump prime funding facilitated (visits and consumable costs) new collaborations with PCube (Grenoble), Imperial College protein production facility and the Oxford protein production facility.
Start Year 2012
 
Description Inflammation collaborations 
Organisation GlaxoSmithKline (GSK)
Department Research and Development GSK
Country United Kingdom 
Sector Private 
PI Contribution The MCBN provided collaborative pump prime funding to David Ray, and Andrew Loudon to develop relationships with GSK in North Carolina. This has led to two grant applications: ?Calling time on inflamed fat: targeting the biological clock in obesity-related inflammation? submitted to MRC (David Ray PI, £600K), and ?Local and systemic circadian cues co-ordinately regulate innate immunity via an epigenetic circuit? submitted to BBSRC with GSK (Andrew Loudon PI, £560K). Short term research projects co-funded by the MCBN have led to grant applications to RCUK to extend these collaboration.
Start Year 2011
 
Description Rational design of formulation screens 
Organisation University of Manchester
Country United Kingdom 
Sector Academic/University 
PI Contribution A cross disciplinary collaboration to explore ?Rational design of formulation screens using peptide-based inhibitors of non-specific protein self association; potential excipients for formulation of protein therapeutics? was funded through a pump priming MCBN award.
Start Year 2012
 
Description Synthesis of an organelle-specific inhibitor of deubiquitinating enzymes 
Organisation University of Manchester
Country United Kingdom 
Sector Academic/University 
PI Contribution The MCBM provided pump prime funding to enable growing collaborations between interdisciplinary Chemistry and FLS research groups. Results of the novel collaborative work will provide the foundation for grant applications as well as high impact publications.
Start Year 2012
 
Description Understanding aggregation 
Organisation Lonza Group
Country Global 
Sector Private 
PI Contribution The MCBN network brought together groups from across campus and Lonza resulting in a joint grant LINK proposal submitted in April 2013 ?Understanding how aggregation influences the immune response to recombinant protein therapeutic drugs?. £460K. This work was also supported by pump prime funding from the MCBN. The MCBN funding helped to develop cross campus collaborations between interdisciplinary research groups and with Lonza. Grant application to continue this research collaboration has been submitted for a MRC LINK grant.
Start Year 2013
 
Description Computational Chemistry Conference 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Held on 13th Sept. 2012 this network meeting, hosted by Richard Bryce and co-sponsored by the MCBN, Dotmatics, Chemical Computing Group, and Molecular Graphics and Modelling Society, the one day event had 8 speakers who covered a range of chemical biology topics, based around development and application of computer-aided molecular design methods. Attended by approx. 80 delegates the day also provided an opportunity to network over a lunchtime poster session.

A good networking meeting which lead to collaborative research secondment to Bryce's lab in Aug 2013

This networking event resulted in new collaborative activity, across campus, nationally and between academic and industrial members of the network.
Year(s) Of Engagement Activity 2012
 
Description Launch of the MCBN 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Launch event hosted on 19th May 2011 brought together the research groups from across the network and MCBN industrial partners. The one day event saw 6 short talks from MCBN academics and GSK, Pfizer, AZ, Imagen Biotech and Syngenta with a poster session over lunch. The networking event introduced the aims of the network to forge collaborations. (Attended by approx 125 people).

This networking event resulted in new collaborative activity, across campus, nationally and between academic and industrial members of the network.
Year(s) Of Engagement Activity 2011
 
Description MCBN Sandpit meeting I 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Held on 27th June 2011 this was an afternoon networking discussion meeting to explore common interests across the MCBN networks in the areas of: Protein:Protein interactions; Protein Trafficking; Novel Chemistry Scaffolds; Ion Channels; Nuclear receptor modulators/deorphanisation and Phosphatases.

This networking event resulted in new collaborative activity, across campus, nationally and between academic and industrial members of the network.
Year(s) Of Engagement Activity 2011
 
Description MCBN Sandpit meeting II 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact The one day networking event, held on 17th January 2012, was attended by approx 75 people from across UoM and industry. The event highlighted research from across the network with invited key note presentations from Paul Brennan (Oxford University) and Ali Travassoli (University of Southampton) and a poster session over lunch.

This networking event resulted in new collaborative activity, across campus, nationally and between academic and industrial members of the network.
Year(s) Of Engagement Activity 2012
 
Description MCBN Sandpit meeting III 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Held on 21st June 2012 this networking event hosted an afternoon program of talks from across the network with key note talks from Philip Cohen (Univ. Dundee), Michael Overduin (Univ. Birmingham) and David Spring (Univ. Cambridge).

This networking event resulted in new collaborative activity, across campus, nationally and between academic and industrial members of the network.
Year(s) Of Engagement Activity 2012
 
Description Phosphatases in Drug Discovery 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact This one day event (20/04/2012) brought together national phosphatase experts (40 invited attendees) to discuss current challenges, tools and assets, and opportunities for targeting phosphatases in drug discovery. The day had keynote talks from Nick Tonks (CHSL), Tricia Cohen (Dundee) and Andy Morley (Dundee) with discussion sandpits. A steering group to look at future direction of phosphatase initiatives nationally was set up and met on a number of occasions.

This networking event resulted in new collaborative activity, across campus, nationally and between academic and industrial members of the network.
Year(s) Of Engagement Activity 2012