Engineering RiPP pathways: strategies for generating complex bioactive peptides

Historically, natural products have been essential sources of therapeutic agents, many of which are currently used to manage various diseases. In recent years, ribosomally synthesized and post-translationally modified peptides (RiPPs) have garnered considerable interest in drug discovery and development due to their biosynthetic plasticity and their ability to generate diverse bioactive structural scaffolds. Unfortunately, many RiPPs have suboptimal bioavailability and proteolytic stability, significantly limiting their clinical potential. Moreover, the complexity of RiPP structures makes total synthesis extremely difficult. These drawbacks necessitate pathway engineering to create derivatives with potentially optimized physicochemical properties. Herein, we review recent efforts to surmount pathway engineering challenges and to rationally modify components of RiPP pathways for new functions to derive new bioactive analogs.