A Biocatalysis-ChemoCascade Approach to Complex Bioactive Molecular Scaffolds

Natural products remain one of the major inspirations behind the successful development of new 'small molecule' tools for chemical biology. The molecular architectures of these naturally occurring molecules are often incredibly intricate as they have evolved over millennia to selectively interact with biological systems. A key challenge for science entails the re-engineering of the structure of these natural leads and the delivery of tools for bioscience and medicine. Unfortunately, the complex architectures of natural products often lie beyond the reach of state-of-the-art synthetic technology.
We will develop a highly innovative chemo-enzymatic approach to the expedient construction of complex natural product-like molecular architectures: the highly selective enzymatic oxidation of readily accessible chemical feedstocks using a toolbox of biocatalysts (Turner) will provide chiral substrates for powerful cyclization cascades using chemical catalysts (Procter). The unique strategy combines cutting edge biocatalysis and chemocatalysis in a powerful, synergistic approach to complex molecular scaffolds for biological evaluation. For example, we will deliver novel analogues of the complex natural phorbol esters, well-established biological research tools in carcinogenesis, T-cell activation, proliferation, and cytokine production and staining. The coupled chemo-enzymatic approach to molecular libraries that exhibit natural product-like molecular architectures will deliver next-generation molecular tools for the advancement of chemical biology in industry and academia.
The team features world leaders in the development and exploitation of new synthetic technology (Procter) and the harnessing of wild type and mutant enzymes (Turner). The student will receive training in a number of state-of-the-art techniques including directed enzyme evolution, development of high-throughput assays, advanced asymmetric and target synthesis.