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Fluorescent HTS Assays for Methyltransferases in Neurodegenerative Diseases

Award Information

Agency:
Department of Health and Human Services
Branch:
N/A
Award ID:
80290
Program Year/Program:
2008 / SBIR
Agency Tracking Number:
GM073290
Solicitation Year:
N/A
Solicitation Topic Code:
N/A
Solicitation Number:
N/A
Small Business Information
BELLBROOK LABS, LLC
5500 NOBEL DR, STE 230 MADISON, WI -
View profile »
Woman-Owned: No
Minority-Owned: No
HUBZone-Owned: No
 
Phase 2
Fiscal Year: 2008
Title: Fluorescent HTS Assays for Methyltransferases in Neurodegenerative Diseases
Agency: HHS
Contract: 2R44GM073290-02
Award Amount: $822,148.00
 

Abstract:

DESCRIPTION (provided by applicant): Methylation is a ubiquitous and reversible covalent modification used to control the function of diverse biomolecules including their activity, stability and localization. Like phosphorylation, methylation is used to mo dulate protein function, but in addition many small molecules are regulated by methylation including hormones, neurotransmitters, xenobiotics, and lipids. More than 50 distinct methyltransferase (MT's) enzymes are present in humans, and not surprisingly th ey are emerging as therapeutic targets for a broad range of diseases. Their involvement in neurodegenerative disease pathways is of special relevance because of the central role that methylation plays in regulating neurotransmitter function. The developmen t of highly selective MT modulators is clearly a compelling medical priority. However, efforts to achieve this are being hampered by a lack of robust, flexible enzyme assay methods adaptable to high throughput screening (HTS). To address this need, in Phas e I BellBrook Labs developed a novel fluorescence polarization immunoassay for S-adenosylhomocysteine (SAH), the invariant product of all MT reactions. This required development of a highly selective antibody that is able to differentiate between SAH and t he substrate S-adenosylmethionine on the basis of a single methyl group. The Transcreener MT assay enables detection of any MT with any acceptor substrate in a homogenous format - and without the use of coupling enzymes - thus it eliminates all of the shor tcomings associated with alternative methods. In Phase II we propose to 1) rapidly commercialize a first generation, fluorescence polarization-based Transcreener MT assay based of the polyclonal antibodies developed in Phase I, 2) increase flexibility and ease-of-use for the MT assay by using targeted mutagenesis of recombinant IgG clones to increase antibody selectivity for SAH, 3) increase HTS market penetration by formatting the assay for a second commonly used fluorescent detection mode, TR-FRET, and 4) use the novel MT assay combined with in silico screening to develop isoform selective inhibitors for five small molecule methyltransferases. The availability of robust, generic fluorescent HTS assay methods and selective chemical probes for MT's should gr eatly accelerate their validation as drug targets and movement into the pharma drug discovery pipeline.

Principal Investigator:

Robert G. Lowery
6082274501
BOB.LOWERY@BELLBROOK-LABS.COM

Business Contact:


bob.lowery@bellbrooklabs.com
Small Business Information at Submission:

BELLBROOK LABS, LLC
5500 Nobel Drive Suite 250 MADISON, WI 53711

EIN/Tax ID: 043661356
DUNS: N/A
Number of Employees: N/A
Woman-Owned: No
Minority-Owned: No
HUBZone-Owned: No