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

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 1R43AT009419-01
Agency Tracking Number: R43AT009419
Amount: $225,000.00
Phase: Phase I
Program: SBIR
Solicitation Topic Code: R
Solicitation Number: PA15-269
Solicitation Year: 2015
Award Year: 2017
Award Start Date (Proposal Award Date): 2017-01-15
Award End Date (Contract End Date): 2018-01-14
Small Business Information
Palo Alto, CA 94304-1118
United States
DUNS: 078843373
HUBZone Owned: No
Woman Owned: Yes
Socially and Economically Disadvantaged: No
Principal Investigator
 (650) 799-6872
Business Contact
Phone: (650) 799-2851
Research Institution

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 Bakerandapos 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 P 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 Narrative
The noscapinoids are a class of compounds derived from opium poppy that are used as the
active ingredient in cough medicines and are currently under evaluation to treat a number of
diseases including cancer and neurodegenerative disorders The supply of these chemically
complex drugs is dependent on cultivation and extraction from opium poppy a climate and
disease susceptible drug crop which entails many geographical legal and political concerns
Yeast based production will be developed as alternative secure and cost effective source of
key plant derived medicinal compounds

* Information listed above is at the time of submission. *

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