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

(2017) METABOLIC ENGINEERING. 42. p.185-193
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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 entree 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.
Keywords
PRODUCT BIOSYNTHETIC PATHWAYS, COMBINATORIAL BIOSYNTHESIS, BETA-AMYRIN, TRITERPENOID BIOSYNTHESIS, SACCHAROMYCES-CEREVISIAE, NICOTIANA-BENTHAMIANA, SIRAITIA-GROSVENORII, SAPONIN BIOSYNTHESIS, STRUCTURAL DIVERSITY, TRANSIENT PRODUCTION, Transient plant expression technology, Synthetic biology, Terpenes, Triterpenoids, Combinatorial biosynthesis, Drug discovery

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Chicago
Reed, James, Michael J Stephenson, Karel Miettinen, Bastiaan Brouwer, Aymeric Leveau, Paul Brett, Rebecca JM Goss, Alain Goossens, Maria A O’Connell, and Anne Osbourn. 2017. “A Translational Synthetic Biology Platform for Rapid Access to Gram-scale Quantities of Novel Drug-like Molecules.” Metabolic Engineering 42: 185–193.
APA
Reed, J., Stephenson, M. J., Miettinen, K., Brouwer, B., Leveau, A., Brett, P., Goss, R. J., et al. (2017). A translational synthetic biology platform for rapid access to gram-scale quantities of novel drug-like molecules. METABOLIC ENGINEERING, 42, 185–193.
Vancouver
1.
Reed J, Stephenson MJ, Miettinen K, Brouwer B, Leveau A, Brett P, et al. A translational synthetic biology platform for rapid access to gram-scale quantities of novel drug-like molecules. METABOLIC ENGINEERING. 2017;42:185–93.
MLA
Reed, James et al. “A Translational Synthetic Biology Platform for Rapid Access to Gram-scale Quantities of Novel Drug-like Molecules.” METABOLIC ENGINEERING 42 (2017): 185–193. Print.
@article{8528589,
  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 entree 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.},
  author       = {Reed, James and Stephenson, Michael J and Miettinen, Karel and Brouwer, Bastiaan and Leveau, Aymeric and Brett, Paul and Goss, Rebecca JM and Goossens, Alain and O'Connell, Maria A and Osbourn, Anne},
  issn         = {1096-7176},
  journal      = {METABOLIC ENGINEERING},
  keywords     = {PRODUCT BIOSYNTHETIC PATHWAYS,COMBINATORIAL BIOSYNTHESIS,BETA-AMYRIN,TRITERPENOID BIOSYNTHESIS,SACCHAROMYCES-CEREVISIAE,NICOTIANA-BENTHAMIANA,SIRAITIA-GROSVENORII,SAPONIN BIOSYNTHESIS,STRUCTURAL DIVERSITY,TRANSIENT PRODUCTION,Transient plant expression technology,Synthetic biology,Terpenes,Triterpenoids,Combinatorial biosynthesis,Drug discovery},
  language     = {eng},
  pages        = {185--193},
  title        = {A translational synthetic biology platform for rapid access to gram-scale quantities of novel drug-like molecules},
  url          = {http://dx.doi.org/10.1016/j.ymben.2017.06.012},
  volume       = {42},
  year         = {2017},
}

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