A 3-year PhD studentship in organic systems chemistry and developing catalytic peptide ligation

The Powner group uses chemical synthesis and systems chemistry to developing novel, robust, green chemical reactions that can improve the synthetic and catalytic strategies available to access key biochemical targets. For example, amide and peptide bond formation is one of the most-important reactions in chemistry and in biology. Amide formation avoiding poor atom economy reagents was identified by the ACS Green Chemical Institute as the top challenge for organic chemistry. To address this challenges, we have developed a novel strategy for selective peptide synthesis. In 2019, we reported the facile, selective coupling of aminonitriles in water to make peptides (Canavelli et al. Nature 2019, 571, 546). Demonstrating the unique reactivity of aminonitriles could be coupled with biomimetic N-to-C terminal peptide synthesis. In 2020 we reported the first prebiotic synthesis of cysteine (Foden et al. Science 2020, 370, 865), then with cysteine in hand, we discovered Catalytic Peptide Ligation (CPL). Our novel peptide ligation exhibits outstanding chemo- and regio-selectivity for proteinogenic peptides, tolerating all twenty proteinogenic sidechain residues. CPL requires no activating agents - activation is built into the thermodynamically activated but kinetically stable nitrile substrate. CPL demonstrates robust, easy-to-synthesize, stable nitriles can replace difficult-to-synthesize, unstable thioesters in peptide ligation. A key goal of this project will be to build on CPL by developing a novel strategy to programme catalytic activation of both peptides and nucleic acids. This goal aims to advance our understanding of the origins of the central dogma of molecular biology, and develop a novel methodology for orthogonally controlled organocatalytic synthesis of peptides and nucleic acids in water. The student will develop chemical reaction make peptides and oligonucleotides, focusing on the application of kinetically stable activation strategies and biomimetic reactivity for protecting-group-free synthesis.