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

Powner小组使用化学合成和系统化学来开发新颖、稳健、绿色化学反应，这些反应可以改善可用于获得关键生化目标的合成和催化策略。例如，酰胺和肽键的形成是化学和生物学中最重要的反应之一。ACS绿色化学研究所将避免原子经济性差的试剂的酰胺形成确定为有机化学的首要挑战。为了应对这一挑战，我们开发了一种选择性肽合成的新策略。在2019年，我们报告了在水中容易地选择性偶联氨基腈以制备肽（Canavelli et al. Nature 2019，571，546）。证明氨基腈的独特反应性可以与仿生N至C末端肽合成偶联。在2020年，我们报道了第一个半胱氨酸的益生元合成（Foden et al. Science 2020，370，865），然后利用半胱氨酸，我们发现了催化肽连接（CPL）。我们的新肽连接表现出出色的化学和区域选择性的蛋白质肽，容忍所有20个蛋白质侧链残基。CPL不需要活化剂-活化是建立在化学活化但动力学稳定的腈底物中。CPL证明了稳健的、易于合成的、稳定的腈可以在肽连接中取代难以合成的、不稳定的硫酯。该项目的一个关键目标是通过开发一种新的策略来编程肽和核酸的催化活化，从而建立CPL。这一目标旨在促进我们对分子生物学中心法则起源的理解，并开发一种新的方法，用于在水中正交控制有机催化合成肽和核酸。学生将开发化学反应，使肽和寡核苷酸，侧重于应用动力学稳定的活化策略和仿生反应的保护基团自由合成。

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.