Natural sources have been highly important for the discovery of new drugs, offering natural products that possess exciting and potent bioactivities. The development and optimization of many promising natural products relies on introducing bespoke changes through total or semi-synthesis of these compounds, which is a formidable task that hampers our progress. A new class of natural products is emerging as a large, promising superfamily: ribosomally synthesized and post-translationally modified peptide (RiPP) natural products. As the name suggests, the starting material for the biosynthesis of these compounds is a genetically encoded short peptide that gets produced by the ribosome. A cascade of enzymes then transforms these ordinary peptides into extraordinary molecules, which offer a plethora of different, promising bioactivities and highly diverse scaffolds. The remarkable advances in our ability to alter DNA allow us to create libraries of RiPPs by modifying the gene encoding the starting material. This allows the biosynthetic production of derivatives that can be screened for improved properties. In principle, the combination of different RiPP pathways should be possible to create new-to-nature RiPPs by allowing enzymes to work together that normally could not. Proof-of-principle for this approach has been published by ourselves and others.
This project aims to develop technologies to achieve the facile production of new-to-nature RiPP libraries to discover the next generation of therapeutics and diagnostics and pursues complementary approaches towards this end.
The successful completion of this project will revolutionize the design of RiPPs inspired next generation libraries with diverse scaffolds for application in tool compound development, target identification and drug discovery.
