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Recognition and Cleavage of Biological Phosphates – Molecular Recognition, Mechanism and Biomedical Applications

Final Report Summary - PHOSCHEMREC (Recognition and Cleavage of Biological Phosphates – Molecular Recognition, Mechanism and Biomedical Applications)

Chemical research is constantly invigorated by the myriad challenges that present themselves at its interface with biology. Recent advances in structural biology, genome projects, recombinant DNA technology etc. are providing unprecedented opportunities to influence and decipher the molecular basis of life. As a consequence the new field of Chemical Biology is now emerging at the boundaries between chemistry and molecular and cell biology. Here, chemistry generates the means to both understand and influence biological systems by providing probes and reagents – from analytical methods to drugs - and these chemical inventions are as important as understanding the biology. This area will be populated with scientists who think both as chemists and biologists, with a strong quantitative understanding of both areas – giving rise to a new, supradisciplinary field that unites the classically separate disciplines of Chemistry and Biology. The objective of this network was to train individuals to meet these challenges.

The scientific focus of this network is the recognition of the ubiquitous biological phosphate group and its transfer reactions that are responsible for a variety of biological regulation mechanisms. The network comprised a variety of research groups to enable a synoptic study of natural and biomimetic systems and emphasised mechanistic studies and in-depth comparison of existing and new systems, ranging from enzyme, enzyme models to transcriptional regulators and gene therapy technologies

The research training challenge of this project was to address interdisciplinary questions using biophysical, biochemical and organic synthesis approaches to acquire insight into fundamental questions concerning molecular recognition and the biological roles of existing and newly synthesised systems. The network organised training and transfer of knowledge in ways that are better suited to contemporary science in academia and industry: many of the routine techniques used in the partner labs could not have been performed 10 years ago. By contrast we will educate a generation of scientists for whom interdisciplinary work between molecular biology, biology and chemistry has become second nature, which will have a lasting long-term effect on science and the economy in Europe.

• A series of structured workshops addressed the critical need of advanced further education that is most crucial for a globally competitive economy. Undergraduate courses have a hard time incorporating such new knowledge and, even if they were able to update course structures, the sort of detailed specialist knowledge will simply not fit in a general biology or chemistry course. We met this unmet need by providing hands-on experimental and classroom teaching in the following areas:

1. Kinetic and mechanistic analysis of complicated bioorganic and enzymatic systems
2. Chemical reactions of nucleic acids
3. Metal ion chelates as catalysts, structural probes and reporters
4. RNA handling techniques – RNA secondary structure mapping by SHAPE and in-line probing, including practical exercises
5. Synthesis and specific applications of modified peptides and oligonucleotides
6. Linear-free energy relationships (Brønsted plots) and isotope effects as indicators of mechanism
7. Multivalent systems, molecular recognition and catalysis
8. Nucleic acids as therapeutic and diagnostic agents - present status, future prospects and challenges
9. Drug development
10. Computational approaches
11. Entrepreneurial awareness - Invention-to-market-workshop
12. Intellectual property workshop
13. Career workshop - covering academic, industry and entrepreneurial start up
14. Grant writing workshop

• The main vehicle of hands-on research training was the exchange of young researchers between groups and the establishment of genuine collaborative efforts.

• Regular updates of projects and of current research inside and outside the network was provided by regular network meetings.

In setting up this Network, we have put emphasis on the diverse background of the participant groups ranging from industrial research (07,08) to chemistry (04, 05, 06, 02) and biological chemists/molecular biologists (03b, 01, 09). All of these are leaders in their respective fields: the representative publications tell a clear story.

• The interdisciplinary research projects have encouraged young scientists to think and work across the boundaries of conventional disciplines. New lines of research have been developed in this network that are anticipated to have future economic impact, e.g. by foundation of a spin-off company originating from network researchers’ projects (Oligomer Sciences, Stockholm).

Specific highlights of research advances that were the result of the research training programme carried out by the young researchers:

– Insight into phosphate transfer mechanisms derived from man-made chemical models and natural catalysts allows rational manipulation of a crucial class of biologically relevant enzymes
– Chemical systems with designed molecular recognition features successfully bind nucleic acid targets and are being combined with cleavage moieties
– The therapeutic prospects of phosphate binders or cleavers is critically dependent on their cellular delivery. Therefore drug-delivery systems have been constructed (e.g. cell penetrating and antisense oligonucleotides) and successfully used in mammalian cells with relevance to disease models
– Development of easy-to-use ultra high-throughput screening systems for enzyme selections from man-made and metagenomic libraries. This approach allows combinatorial manipulation of biocatalyst and complements the design-led efforts described above.

NB In October 2014 the PhosChemRec website will move along with the Hollfelder group website to https://www.bioc.cam.ac.uk/hollfelder/research/phcrfront