Ribosomally synthesized and post-translationally modified peptide natural products (RiPPs) are a rapidly growing class of peptide derived natural products. RiPP enzymes carry out remarkable chemistry en route to transforming short peptides into bioactive molecules. RiPP enzymes are also remarkably promiscuous: guided by short recognition sequences, they are capable of modifying multiple residues within a single peptide and accepting many non-natural substrates. We have recently been able to harness these unique and versatile enzymes for use as biocatalysts in the synthesis and investigation of new peptide therapeutics. Two examples will be presented. First, by employing members of the new pyridine synthase family of macrocyclases, discovered in our lab, we create non-natural analogues of the potent antibiotics known as thiopeptides to explore their structure activity relationships. Second, we use these enzymes to create large and diverse genetically-encoded libraries of natural product-like peptide macrocycles. These libraries can be screened and effectively “evolved” on the benchtop to identify inhibitors of some of the most intractable therapeutic targets.
Dr. Bowers obtained his BA from the University of Chicago and went on to complete his Ph.D. in organic chemistry in 2007, at the University of Illinois at Chicago, under the guidance of Prof. David Crich. He was an NIH postdoctoral fellow in the labs of Professor Robert M. Williams at Colorado State University and Professor Christopher T. Walsh at Harvard Medical School. After spending a year as Assistant Professor at Purdue University, he joined the faculty of Chemical Biology and Medicinal Chemistry at the University of North Carolina at Chapel Hill in 2012. His lab engineers biosynthetic pathways and develops chemoenzymatic strategies to generate next-generation therapeutics.