Projektbeschreibung
Neuartige Peptide mit hoher Bioaktivität
Ribosomal synthetisierte und posttranslational modifizierte Peptide (RiPP) sind in ihrer Struktur vielfältige Naturprodukte, deren Biosynthese auf großes Interesse gestoßen ist. Ihre chemische Vielfalt ergibt sich aus umfangreichen posttranslationalen Modifikationen eines Vorläuferpeptids. Im Rahmen des EU-finanzierten Projekts EXPLORE sollen neue Ansätze für die Herstellung maßgeschneiderter RiPP entwickelt werden. Die Forschenden wollen sich nicht-natürliche Aminosäuren und andere Bausteine zunutze machen, um hybride RiPP in vitro herzustellen. Anschließend werden sie diese Technologie in Escherichia coli anwenden, um mithilfe der Genetik große Bibliotheken von Verbindungen herzustellen. Es wird erwartet, dass die erzeugte Serie von RiPP-Gerüsten in der Arzneimittelforschung Anwendung finden wird.
Ziel
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.
Wissenschaftliches Gebiet
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Finanzierungsplan
ERC-COG - Consolidator GrantGastgebende Einrichtung
30167 Hannover
Deutschland