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Selection-driven plant metabolites for treatment of CNS diseases

Award Number: R44AA018226
ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2009
PERIOD OF PERFORMANCE END DATE: 02/28/2017

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Selection-driven plant metabolites for treatment of CNS diseases - DESCRIPTION (provided by applicant): This project aims to demonstrate that the evolution of plant biosynthetic pathways can be accelerated and driven to favor the synthesis of ligands which interact with a specific human target protein. This is achieved by subjecting mutant plant cells to selection pressures favoring the survival of mutants with the phenotype of interest. As an example, this approach will be used to optimize pharmacological activity in Lobelia cardinalis, which inhibits the human dopamine transporter (hDAT), putatively by its ability to synthesize the complex alkaloid, lobinaline. A stable transgenic line of L. cardinalis plant cells expressing the hDAT has been established. These cells show increased sensitivity to toxins transported into the cell by the hDAT, including the neurotoxin MPP+. A large, genetically diverse, population of gain-of-function mutants expressing the hDAT has now been generated, and selected on medium containing 100uM MPP+, which kills the vast majority of the transgenic mutants. However, individual mutants that are over-producing inhibitors of the hDAT have a survival advantage, so that the MPP+-resistant population is greatly "enriched" in clones with this bioactivity. Preliminary GC/MS analysis of individual MPP+-resistant mutants with increased hDAT inhibitory activity indicates that many of these are overproducing lobinaline, but the rest are generating other metabolites, some of which are not detectable in the wild-type plant. Phase II is designed to demonstrate that this biotechnology can be used to (a) generate novel natural products with a specific valuable pharmacology (b) provide a biosynthetic production system for these compounds in mutant plants. The process should be of particular value when a plant-derived lead compound, such as lobinaline, is too complex for chemical synthesis. The first specific aim is to analyze the remaining MPP+-resistant population to determine those individuals in which lobinaline content cannot explain increased hDAT inhibitory activity. Separation (assay-guided preparative HPLC) and tentative identification (GC/MS) of active compounds will be followed by pharmacological evaluation in vitro, in comparison with lobinaline and a synthetic inhibitor of the hDAT. The most active compounds will then be tested for functional effects on the DAT in rat brain in vivo using electrochemistry. In parallel studies, the mutant clonal cultures which are overproducing active metabolites to the greatest extent will be regenerated to intact mutant plants, and extracts analyzed to establish whether the pharmacological /chemical phenotype is retained. The ultimate aim is to commercialize the technology as a platform for discovering and producing novel plant-derived natural products targeted on specific human CNS proteins.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2017 ( Subtotal = -$308,909 )
2017	2015	NAPROGENIX, INC.	UK-ASTECC 145 GRAHAM AVE	LEXINGTON	KY	40506	FAYETTE	USA	Alcohol Research Programs	001	4	8/23/2017	SUPPLEMENT FOR EXPANSION	-$98,469
2017	2014	NAPROGENIX, INC.	UK-ASTECC 145 GRAHAM AVE	LEXINGTON	KY	40506	FAYETTE	USA	Alcohol Research Programs	000	4	8/23/2017	NON-COMPETING CONTINUATION	-$210,440
														Subtotal = -$308,909

Issue Date FY: 2016 ( Subtotal = $0 )
2016	2015	NAPROGENIX INC	1401 UNIVERSITY DRIVE	LEXINGTON	KY	40546	FAYETTE	USA	Alcohol Research Programs	001	4	8/4/2016	SUPPLEMENT FOR EXPANSION	$0
2016	2014	NAPROGENIX INC	1401 UNIVERSITY DRIVE	LEXINGTON	KY	40546	FAYETTE	USA	Alcohol Research Programs	000	4	8/4/2016	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2015 ( Subtotal = $98,469 )
2015	2015	NAPROGENIX INC	1401 UNIVERSITY DRIVE	LEXINGTON	KY	40546	FAYETTE	USA	Alcohol Research Programs	000	4	3/23/2015	SUPPLEMENT FOR EXPANSION	$98,469
														Subtotal = $98,469

Issue Date FY: 2014 ( Subtotal = $487,620 )
2014	2014	NAPROGENIX INC	1401 UNIVERSITY DRIVE	LEXINGTON	KY	40546	FAYETTE	USA	Alcohol Research Programs	000	4	8/8/2014	NON-COMPETING CONTINUATION	$487,620
														Subtotal = $487,620

Issue Date FY: 2013 ( Subtotal = $516,666 )
2013	2013	NAPROGENIX INC	1401 UNIVERSITY DRIVE	LEXINGTON	KY	40546	FAYETTE	USA	Alcohol Research Programs	000	3	9/9/2013	COMPETING CONTINUATION	$516,666
														Subtotal = $516,666

Grand Total All Awards = $793,846

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Selection-driven plant metabolites for treatment of CNS diseases

Award Number: R44AA018226

ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 01/01/2009

PERIOD OF PERFORMANCE END DATE: 02/28/2017

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