A translational synthetic biology platform for rapid access to gram-scale quantities of novel drug-like molecules

Reed, James, Stephenson, Michael J ORCID: https://orcid.org/0000-0002-2594-1806, Miettinen, Karel, Brouwer, Bastiaan, Leveau, Aymeric, Brett, Paul, Goss, Rebecca J M, Goossens, Alain, O'Connell, Maria A ORCID: https://orcid.org/0000-0002-0267-0951 and Osbourn, Anne (2017) A translational synthetic biology platform for rapid access to gram-scale quantities of novel drug-like molecules. Metabolic Engineering, 42. 185–193. ISSN 1096-7176

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Abstract

Plants are an excellent source of drug leads. However availability is limited by access to source species, low abundance and recalcitrance to chemical synthesis. Although plant genomics is yielding a wealth of genes for natural product biosynthesis, the translation of this genetic information into small molecules for evaluation as drug leads represents a major bottleneck. For example, the yeast platform for artemisinic acid production is estimated to have taken >150 person years to develop. Here we demonstrate the power of plant transient transfection technology for rapid, scalable biosynthesis and isolation of triterpenes, one of the largest and most structurally diverse families of plant natural products. Using pathway engineering and improved agro-infiltration methodology we are able to generate gram-scale quantities of purified triterpene in just a few weeks. In contrast to heterologous expression in microbes, this system does not depend on re-engineering of the host. We next exploit agro-infection for quick and easy combinatorial biosynthesis without the need for generation of multi-gene constructs, so affording an easy entrée to suites of molecules, some new-to-nature, that are recalcitrant to chemical synthesis. We use this platform to purify a suite of bespoke triterpene analogs and demonstrate differences in anti-proliferative and anti-inflammatory activity in bioassays, providing proof of concept of this system for accessing and evaluating medicinally important bioactives. Together with new genome mining algorithms for plant pathway discovery and advances in plant synthetic biology, this advance provides new routes to synthesize and access previously inaccessible natural products and analogs and has the potential to reinvigorate drug discovery pipelines.

Item Type:	Article
Additional Information:	Copyright © 2017. Published by Elsevier Inc.
Uncontrolled Keywords:	transient plant expression technology,synthetic biology,terpenes,triterpenoids,combinatorial biosynthesis,drug discovery
Faculty \ School:	Faculty of Science > School of Biological Sciences Faculty of Science > School of Pharmacy (former - to 2024) Faculty of Science > School of Chemistry (former - to 2024)
UEA Research Groups:	Faculty of Science > Research Groups > Molecular and Tissue Pharmacology Faculty of Science > Research Groups > Chemistry of Life Processes
Depositing User:	Pure Connector
Date Deposited:	12 Jul 2017 05:05
Last Modified:	11 Nov 2024 00:45
URI:	https://ueaeprints.uea.ac.uk/id/eprint/64081
DOI:	10.1016/j.ymben.2017.06.012

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