Exploitation of enzyme promiscuity to generate ribosomal natural product diversity

Projektinformationen

EXPLORE

ID Finanzhilfevereinbarung: 101002326

DOI

10.3030/101002326

EK-Unterschriftsdatum 16 Februar 2021

Startdatum 1 Juni 2021

Enddatum 31 Mai 2027

Finanziert unter

• EXCELLENT SCIENCE - European Research Council (ERC)

Gesamtkosten

€ 1 977 125,00

EU-Beitrag

€ 1 977 125,00

Koordiniert durch

GOTTFRIED WILHELM LEIBNIZ UNIVERSITAET HANNOVER
Germany

Periodic Reporting for period 3 - EXPLORE (Exploitation of enzyme promiscuity to generate ribosomal natural product diversity)

Berichtszeitraum: 2024-06-01 bis 2025-11-30

Zusammenfassung vom Kontext und den Gesamtzielen des Projekts

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.

Arbeit, die ab Beginn des Projekts bis zum Ende des durch den Bericht erfassten Berichtszeitraums geleistet wurde, und die wichtigsten bis dahin erzielten Ergebnisse

In the first part of our project, we have built the necessary genetic tools and circuits to allow us to pursue our overall goal. We have also successfully generated the first libraries and identified a novel natural product derivative able to bind to a protein important in a variety of human cancers. We are now working with a partner to use our discovery to develop a novel diagnostic test.

Fortschritte, die über den aktuellen Stand der Technik hinausgehen und voraussichtliche potenzielle Auswirkungen (einschließlich der bis dato erzielten sozioökonomischen Auswirkungen und weiter gefassten gesellschaftlichen Auswirkungen des Projekts)

Unfortunately, this cannot be published until the patent has been filed.

Concept of ERC grant EXPLORE