Cross-Electrophile Coupling Strategies for the Synthesis of RiPP Natural Products

Emory University, Atlanta GA

Investigators

Abstract

With the support of the Chemical Synthesis program in the Division of Chemistry, Professor Simon Blakey of Emory University will study the development of new methods and enabling strategies to make ribosomally synthesized post-translationally modified peptides (RiPPs). RiPPs are macrocyclic peptide architectures that have been recognized as important in drug discovery, particularly due to their ability to target relatively featureless flat surfaces on target proteins that were once considered “undruggable”. Despite their promise, their unique architectures continue to pose significant synthetic challenges and currently no general strategies to RiPPs exist, limiting their further development. The major goal of this research is to develop a universal catalytic platform to enable the synthesis of any RiPP natural product in this class. Key to this strategy is the development of modular building blocks that will made broadly available, and the methods will be compatible with established automated peptide synthesizers to enable access to these compounds by non-specialists. The theme of automated synthesis is closely associated with the emerging concept of “self-driving labs”, which integrate modern robotics and machine learning technologies and have the potential to revolutionize the way in which new medicines are discovered. An Interdisciplinary Future Scientists Lunch Series will aim to educate both graduate and undergraduate students on the importance of integrating automation, high-throughput experimentation, “big-data”, and machine learning to advance discovery in the chemical sciences. This project aims to develop a general synthetic platform to ribosomally synthesized post-translationally modified peptides (RiPPs) through the advancement of novel cross electrophile coupling reactions. Key to this approach is the development of novel stereoselective C(sp2)–C(sp3) coupling reactions for unactivated secondary alkyl halides, which will forge the predominant class of crosslinks found in these RiPP natural products. Methods to access the required beta-bromo amino acids will also be developed, primarily through biocatalysis. The coupling partners developed will be made broadly available and the methods are targeted for applicability to solid phase peptide synthesis. Total syntheses of representative natural products, streptide, ryptide, and the tryglysins will be developed. These syntheses will result in stereochemical determinations for two of the three natural products and provide a road map for others to synthesize emerging members of this natural product family. These RiPP natural products are often linked to quorum sensing pathways, and in many cases exhibit antimicrobial activity, highlighting them as important targets as we face the growing threat of antibiotic resistant pathogens. This research will advance our ability to access both the natural products, and functionalized analogues for SAR and chemical biology studies, facilitating both basic and translational research. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.