Enzymes perform essential reactions that sustain life with un-matched specificity and selectivity. Foldamers provide an opportunity to mimic Nature’s best catalysts as they are conformationally ordered structures that resemble proteins or enzymes. However, costly and time-consuming synthetic efforts have yielded only a small set of foldamers that exhibit poor catalytic activity in water. Here, we propose to combine for the first time Dynamic Combinatorial Chemistry (expertise of the host) and high-throughput screening methods (expertise of the ER) to identify a catalytically active foldamer that operates fully in aqueous solutions. The catalytic foldamer will emerge, with little synthetic effort, from a Dynamic Combinatorial Library (DCL) which contains building blocks that display key catalytic centers. The emerging foldamers will be tested for catalytic activity (e.g. hydrazone formation, ester hydrolysis) using newly-developed UPLC/UV-vis/fluorescence high-throughput protocols. This will allow rapid screening across a large substrate scope and range of experimental conditions, leading to the identification of foldamers that exhibit weak catalytic function. The activity of these hit foldamers will be optimized by combining different building blocks with optimized structures. Screening will be done in an iterative fashion to quickly survey the possible foldamer structural landscape generated from a mixture of two (or more) building blocks. The resulting data will allow essential design rules to be formulated regarding the relationship between building block structure/library components and catalytic activity. The three-dimensional structure of the discovered catalytic foldamers will be confirmed by X-ray crystallography (expertise of the secondment host).
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