Descrizione del progetto
Nuovi peptidi con potente bioattività
I peptidi ribosomicamente sintetizzati e modificati dopo la traduzione (RiPPs, ribosomally synthesised and post-translationally modified peptides) sono prodotti naturali strutturalmente diversi la cui biosintesi ha suscitato grande interesse. La loro diversità chimica emerge da ampie modificazioni post-traduzionali di un peptide precursore. Il progetto EXPLORE, finanziato dall’UE, propone di sviluppare nuovi approcci per generare RiPP su misura. I ricercatori intendono sfruttare gli aminoacidi non naturali e altri elementi costitutivi per la produzione di RiPP ibridi in vitro e successivamente applicheranno tale tecnologia nell’Escherichia coli per creare ampie librerie di composti usando il potere della genetica. L’insieme di strutture di RiPP generato dovrebbe trovare applicazione nella scoperta di farmaci.
Obiettivo
Natural sources have been highly important for the discovery of new drugs, offering compounds that possess exciting and potent bioactivities. The development of many promising natural products is significantly hampered by the difficulties associated with the synthesis of novel analogs. The family of ribosomally synthesized and post-translationally modified peptide (RiPP) natural products offers a plethora of different, promising bioactivities and highly diverse scaffolds. I propose to develop two new complementary routes to generate modified, bespoke RiPPs in vitro and in vivo: Interchangeable leader peptide (ILP) technology, which is a novel approach tailored to RiPPs. Every RiPP is produced from a precursor peptide that consists of a core peptide (the eventual natural product) and a pathway-specific recognition sequence that is recognized by parts of the biosynthetic machinery. ILP technology will allow me to swap out recognition sequences and thus combine the biosynthetic machineries from diverse RiPP pathways in a mix-and-match approach to generate new-to-nature, hybrid RiPPs using two routes: (1) We will develop this technology in vitro to take full advantage of non-natural amino acids and other building blocks. (2) We will transfer an optimized, streamlined version to an in vivo setting using peptide ligation in the cytoplasm of E. coli. This will allow us to use the power of genetics to create large libraries of compounds. I will harvest the novel enzymatic modifications enabled by ILPs to generate diverse RiPP scaffolds that contain amino acids, non-natural amino acids, enzymatically modified amino acids and non-a-amino acid building blocks. We will then use ILP technology to identify novel pathoblockers for Pseudomonas aeruginosa. 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.
Campo scientifico
Parole chiave
Programma(i)
Argomento(i)
Meccanismo di finanziamento
ERC-COG - Consolidator GrantIstituzione ospitante
30167 Hannover
Germania