Powerful new methods for the synthesis of peptides: catalytic oxidation reactions tested to the limit

Chemistry is a dynamic subject that is at the centre of many different scientific advances. Organic chemistry is concerned with the reactivity of carbon in all its different forms and can be viewed as the chemistry taking place within living things. Chemists are constantly looking for new ways of designing and building molecules (synthetic chemistry is molecular architecture) and this proposal describes a short and powerful new way of making valuable compounds, based on peptides, by using new catalytic reactions. Peptides are important because they are the sequences of amino acids that are absolutely essential to the processes of life; we are attempting to make peptides in a fundamentally new way that will give us great control over the nature of the structures that we make and which will allow us to make natural and unnatural peptides that can be tested as potential new medicines.
Developing, and testing the limits of, new catalytic reactions is also central to this project, and is also a worthwhile endeavour. The development and application of new catalysts and catalytic systems is important because it makes chemical reactions run faster, and become cleaner with less waste: this is clearly a good thing for industry and also for the environment.

To underscore the importance of the compounds that feature in this proposal, peptides can be found in several drugs that have sales of over 1 billion dollars. The novel chemistry proposed here will provide a new, efficient and powerful way of making peptides using catalysis to control functional group incorporation: this will be of great benefit to both academia and industry. Plans have also been made to screen the compounds that we make for a wide range of biological activity.

Given all of the above, it is imperative that we have novel, efficient and powerful methods for making new peptide derivatives so that we can study and use them.

The beneficiaries of this research outside of academia include: chemical industry including the pharmaceutical industry; the agrochemical industry; the fine chemicals industry. These beneficiaries will be able to exploit the chemistry described in this proposal to achieve the synthesis of peptides and peptide conjugates in a more efficient manner, and it will also allow chemical industry to make new peptide-based compounds that were hitherto difficult to access. Peptide based therapeutics are important and valuable molecules with many uses, especially in healthcare and this new science will allow industry to make the commercially valuable compounds of the future in a new way, giving them a competitive advantage. Each of the beneficiaries above improves the quality of life and the wealth of the nation, through the application of novel organic chemistry. Chemical industry plays a big role in the U.K. economy (2005 UK trade surplus in medicines was £3400 million) and the U.K. still has a very strong pharmaceutical industry (with large, medium and small companies), who all stand to benefit from this methodology. The compounds that are the focus of this work can make an important contribution to the development of new peptide therapeutics; for example there are at least four peptide pharmaceuticals with sales of over 1 billion dollars (for example, Zoladex is a synthetic decapeptide used for the treatment of cancer with > $1 billion sales in 2010).

Clearly, it is important that I engage with potential end-users of this chemistry so that I can ensure the project makes the maximum impact in the most relevant areas of research. I have several plans for publicising our work and for getting industry feedback on our routes to peptide derivatives (and on the most worthwhile target peptide conjugates which will open new avenues of research). The easiest way to publicise our work is to deliver lectures in industrial laboratories, followed by a discussion of the potential applications (I have given 9 such lectures at pharmaceutical companies since 2008 and have invitations to speak at industrial venues in 2012). Since appointment in 1994, I have had many CASE type collaborations with industry and sent over 30 researchers to full-time employment in various industrial chemistry laboratories; so I have many relevant contacts within the industrial organic chemistry community. Other opportunities to publicise our work with the beneficiaries will come from the meetings that I have regularly with industry to discuss ongoing collaborations; I am also a consultant for several pharmaceutical companies which gives me another way to discuss this science. I have been, and will continue to be, very active in publicising our methodology and gaining feedback on useful applications of it.
I was recently awarded the Society of Chemistry and Industry Prize for Process Research (2012), which is sponsred by four major chemical companies and which gives an indication of the high level of interaction that I have with the industrial end-users of my work.

The timescale involved in giving a benefit to the end-users of the research is short (months rather than years): as soon as new routes and new conjugates are developed and publicised then they can be used in industrial laboratories. Clearly, routes to established drug candidates are not changed lightly, and it may take longer to make an impact on a drug development scale compared to a medicinal chemistry setting. However, we expect that the new catalytic oxidation reactions that we develop will have such attendant improvements in efficiency and scalability that this will lead industry to use them. We also anticipate that the new compounds that we develop and the extra possibilities generated for joining complex molecules together will have significant impact in a medicinal chemistry setting.

Details of our plans for future exploitation and collaboration are given in the full PIA plan.