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Accelerating the semisynthesis of alkaloid-based drugs through metabolic engineering

Abstract

Alkaloid-derived pharmaceuticals are commonly semisynthesized from plant-extracted starting materials, which often limits their availability and final price. Recent advances in synthetic biology have enabled the introduction of complete plant pathways into microbes for the production of plant alkaloids. Microbial production of modified alkaloids has the potential to accelerate the semisynthesis of alkaloid-derived drugs by providing advanced intermediates that are structurally closer to the final pharmaceuticals and could be used as advanced intermediates for the synthesis of novel drugs. Here, we analyze the scientific and engineering challenges that must be overcome to generate microbes to produce modified plant alkaloids that can provide more suitable intermediates to US Food and Drug Administration–approved pharmaceuticals. We highlight modified alkaloids that currently could be produced by leveraging existing alkaloid microbial platforms with minor variations to accelerate the semisynthesis of seven pharmaceuticals on the market.

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Figure 1: Microbial production of advanced intermediates for plant alkaloid based pharmaceuticals.
Figure 2: Phenylalanine- and tyrosine-derived pharmaceuticals.
Figure 3: Tryptophan-derived pharmaceuticals.
Figure 4: Proposed semisyntheses of benzylisoquinoline alkaloid-derived FDA-approved pharmaceuticals.
Figure 5: Proposed semisyntheses of morphinan- and pyrroloquinoline-derived FDA-approved pharmaceuticals.
Figure 6: Proposed microbial production of lysergic acid for the semisynthesis of ergot alkaloids..

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Acknowledgements

This work was performed at the Georgia Institute of Technology and was funded by Start-Up funds, a Blanchard Fellowship to P.P.-Y. and a Georgia Institute of Technology Molecular Biophysics and Biotechnology Graduate Assistance in Areas of National Need (GAANN) fellowship provided by the US Department of Education to A.M.E. (grant P200A120190).

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Ehrenworth, A., Peralta-Yahya, P. Accelerating the semisynthesis of alkaloid-based drugs through metabolic engineering. Nat Chem Biol 13, 249–258 (2017). https://doi.org/10.1038/nchembio.2308

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