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

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

Grant Number: 5R35GM125005-09
NIH Institute/Center: NIH
Principal Investigator: Albert Bowers