Biosynthesis of novel and natural plant alkaloid compounds for drug production and discovery

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Abstract Plants produce an exceptional diversity and number of natural products, many of which are unique to the plant kingdom. However, the difficulties in sourcing medicinal compounds from native plant hosts in sufficient quantity and diversity present a critical barrier to supplying existing medicines, identifying new drug candidates, and progressing through the path to FDA- approved pharmaceuticals. Noscapine is an established antitussive API currently under evaluation to treat a number of diseases including cancer and neurodegenerative disorders. Noscapine is only available via extraction from opium poppy and the need to source this compound through a drug crop leads to increased cost and regulation, which could be avoided if an alternative source was developed that was not inherently linked to the production of controlled substances. A novel approach will be developed for sourcing this and related compounds, by engineering noscapine biosynthesis from sugar for the first time in an industrial microbe, Baker's yeast. By utilizing a “clean” host that is highly amenable to metabolic engineering and industrial-scale production, this approach will establish a constant, secure, and abundant supply of noscapine and related medicinal compounds that is free from contaminating controlled substances and unnecessary regulation. The objectives of this Phase I project will be to develop engineered yeast strains that produce high levels of natural and non-natural noscapinoids, secoberberines, and other valuable alkaloids, thereby providing microbial platforms for the biosynthesis of diverse plant- based medicinal compounds. To achieve high-level production of the target alkaloids, the rate- limiting activities of five pathway cytochrome P450 enzymes will be optimized. In addition, substrate-feeding experiments that target the incorporation of both early precursor molecules and later-stage scaffolds, will enable the synthesis of numerous novel, non-natural BIA molecules and provide key information on the substrate promiscuity of the enzymes for later combinatorial engineering strategies. Through the development of a disruptive and safe technology for producing an important class of plant alkaloids, the deliverables from this project will open up access to a diverse array of natural plant alkaloid compounds and an even greater number of non-natural derivatives. The successful completion of this SBIR project will provide proof-of-concept for a new commercial manufacturing process for established plant-based medicines and a combinatorial biosynthesis platform for the generation of novel drug molecules.