Periodic Reporting for period 2 - EXPLORE (Exploitation of enzyme promiscuity to generate ribosomal natural product diversity)
Reporting period: 2022-12-01 to 2024-05-31
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.
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.
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.
Unfortunately, this cannot be published until the patent has been filed.