Chemoenzymatic Synthesis, Mode of Action and Evolution of Natural Product-based Macrocycles

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Chemoenzymatic Synthesis, Mode of Action and Evolution of Natural Product-based Macrocycles (Parent Grant) Natural peptide macrocycles are promising next-generation therapeutics, due to their abilities to bind to challenging protein targets, such as protein interfaces and transcription factors. The goal of our lab is to use insights and chemistries from natural product biosynthesis to facilitate the discovery and development of new natural product-like peptide macrocycles. We will use a combined chemical and enzymatic approach for synthesis and efficient benchtop evolution of highly constrained peptide macrocycles similar to those used in nature. Over the next five years, these efforts will be divided between two main project areas. In the first project area, we will use enzymes take from ribosomal peptide natural product biosynthetic pathways to modify mRNA display libraries of peptides. Essential to this work will be the continued development of display-coupled assays for enzyme modification that will be used to elucidate enzyme promiscuity. In the second project area, these libraries will be used to select novel macrocyclic peptide inhibitors against a focused set of therapeutic targets and complexes. Structural characterization of target-ligand complexes will uncover principles of macrocycle engagement and elucidate new strategies for targeting these otherwise challenging interfaces. This work is expected to yield new avenues and technologies for development of peptide macrocycle-based therapeutics.