Reprogramming RiPP scaffolds through skeletal editing unlocks chemical space

In this study, we report (1) a scalable, systematic, and general synthetic approach for the supply of ribosomally synthesized and post-translationally modified peptides (RiPPs) bearing Tyr-Trp cross-linkages, and (2) the comprehensive expansion of novel chemical space through their skeletal diversification. In recent years, numerous biaryl-containing peptides have been discovered, and some of these RiPPs exhibit potent biological activities. However, despite the high metabolic stability and strong target protein binding generally attributed to biaryl RiPPs, their significant strain and rigidity have limited the availability of general synthetic methods. Here, we demonstrate the high versatility of modular synthetic strategies for the construction of RiPPs and achieve the synthesis of a variety of RiPPs containing Tyr-Trp cross-linkages. Furthermore, skeletal diversification via scaffold hopping enables access to artificial RiPP scaffolds incorporating quinazoline and quinoline motifs, whose preparation has previously been challenging.