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New chemical biology for tailoring novel therapeutics

Final Report Summary - NCB-TNT (New chemical biology for tailoring novel therapeutics)

Cyclic peptides are increasingly recognized as a very important and promising class of future medicines. This is because they possess so called privileged scaffolds, that is to say these molecules are often cell penetrating and biologically potent. Total chemical synthesis of a handful of such molecules has been possible but it can involve over 40 steps, thus making synthesis of libraries of compound impractical. Many of the most interesting molecules exist only in very small amounts from natural sources. Even where they are more readily available, the chemistry to tailor the molecules to ensure they have desirable properties is lacking, so if the molecule is not perfect it cannot be used. These limitations have meant very few of this exciting class of molecules have made it to clinical trials and they are not fully represented in screens for new drugs.
The thrust of the proposal to the ERC was to combine chemistry and biology to make entirely novel hybrid cyclic peptides molecules. Such hybrids would enable us to go beyond the current state of the art and permit the synthesis of small libraries of complex molecules with bespoke properties.
We set four aims in the proposal, first define the enzymatic activity of the macrocyclase, second carry out novel bio transformations, third generate novel peptide substrates to identify targets of patellamides and fourth to demonstrate the ability to combine chemical synthesis with enzyme chemistry enabling split and pool approach.
We have achieved all four aims, we have published papers as part of each aim, that demonstrate objectively our success. In total we have reported twenty six papers, all of which are available on line with two more being written. Our structural data has been made publicly accessible and the genes of engineered proteins made available through a public repository. We have filed three patents with a fourth submitted and due to be published this year. We have spun out a company to commercialise the technology we have developed. We have publicized our science and held events for school children to promote science. We have thus ensured that we have disseminated the knowledge we have gained.
Scientific highlights have included the (1) We reported the molecular characterization of a new class of macrocyclase and engineered substrates that allowed enzymes to be deployed. (2) We designed and realization of an engineered tailoring enzyme that can process non-natural substrates. (3) We characterized new enzyme chemistries including amide methylation that can introduce important modifications into substrates that are almost impossible by other routes. (4) Finally, we brought all our learning together and were able to make a molecules that that contained no natural amino acids and make small libraires of novel molecules by combining chemistry and biology.

ERC funding has transformed my research output and direction. My lab has been recognized by three major awards, Fellowship of the Royal Society, Fellow of the American Association for the Advancement of Science and the Tilden Medal of the Royal Society of Chemistry, all of which relate to the work in this project. This was a bold and ambitious project; it represented a shift in my expertise. I believe it has been very successful.