GCGXC · GenoChemetics: Gene eXpression enabling selective Chemical functionalisation of natural products

We aim to consolidate a trans-disciplinary research programme in which synthetic biology is harnessed to enable synthetic chemistry. We will utilise this approach to expeditiously access series of previously intractable natural product analogues.There is an urgent need for the discovery and development of new drugs and in particular new antibiotics. More than 13 million lives worldwide are currently claimed each year due to infectious diseases. Natural products provide an unparalleled starting point for drug discovery, with over 60% of anticancer agents and over 70% of antibiotics entering clinical trials in the last three decades being based on such compounds. In order to gain a full understanding as to how a drug works and in order to be able to generate compounds with improved biological activity and physicochemical properties the generation of analogues is essential. In recent years pharmaceutical industries have shied away from natural products due to the perceived synthetic intractability of libraries of natural product analogues and the misperception that it is not possible to carry out thorough structure activity relationship (SAR) assessment on such compounds. As a result of largely abandoning natural products, industries’ drug discovery pipelines are beginning to run dry; this is a particular concern when faced with the need to combat the ever-increasing problem of drug resistance and infectious disease.We aim to challenge the misperception that natural products are not “med chemable” We are developing a new approach to natural product analogue synthesis. By introducing a gene from a foreign organism to complement existing natural product biosynthetic machinery we are able to introduce a chemically orthogonal, reactive and selectably chemically functionalisable handle into the natural product (the antithesis of a protecting group) - this reactive handle will enable us to carry out chemical modifications only at the site at which it is located.