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FLUORESCENT G PROTEINS FOR GPCR DRUG DISCOVERY

Award Number: R43GM076845
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: HEALTH SERVICES
PERIOD OF PERFORMANCE START DATE: 03/12/2006
PERIOD OF PERFORMANCE END DATE: 02/28/2007

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FLUORESCENT G PROTEINS FOR GPCR DRUG DISCOVERY - DESCRIPTION (provided by applicant): G protein coupled receptors (GPCRs) constitute the largest family of membrane proteins in the human genome and the largest group of targets for drug discovery. Yet the success rate for developing new effective drugs for specific GPCRs has been disappointing in spite of remarkable scientific advances in the field over the past 20 years. Drug development for GPCRs is frequently limited by insufficient functional information obtained at the level of high throughput screening and lead optimization. High throughput assays for GPCRs are generally cell based and designed for sensitivity, often at the cost of physiologically relevant functional information such as efficacy and G protein coupling specificity. In contrast, assays that directly measure the coupling of receptors to G proteins (such as GTP?S binding assays) provide valuable functional information, but are less amenable to high throughput screening. Moreover, these assays are generally limited to Gi coupled receptors because of relatively low signal to noise for Gs and Gq coupled receptors. The goal of this Phase I proposal is to develop more robust and versatile fluorescence-based assays that directly measure coupling of GPCRs to G proteins. The technical foundation of this proposal is the use of membrane tethered G protein alpha subunits (Tet-Ga) that couple more efficiently to GPCRs than native G proteins. Moreover, they can be efficiently and economically purified and reconstituted with membranes containing GPCRs. We will take advantage of this patented technology to develop sensitive, fluorescence-based assays for use in high-throughput screening and lead development. These assays will have higher commercial value for pharmaceutical companies. Phase I Specific Aims: 1. Generate a modified, functional Tet-Gas with no reactive cysteines. 2. Generate modified G proteins having single reactive cysteines to act as conformationally sensitive reporters. 3. Demonstrate changes in fluorescence properties of labeled, purified Tet-Gas upon activation by a GPCR. If Phase I goals are successful, we will seek Phase II funding to develop high-throughput assays for commercial use.


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: 2006 ( Subtotal = $100,000 )
2006	2006	CONFOMETRX INC	840 CHIMALUS DRIVE	PALO ALTO	CA	94306	SANTA CLARA	USA	Biomedical Research and Research Training	000	1	3/10/2006	NEW	$100,000
														Subtotal = $100,000

Grand Total All Awards = $100,000

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FLUORESCENT G PROTEINS FOR GPCR DRUG DISCOVERY

Award Number: R43GM076845

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: HEALTH SERVICES

PERIOD OF PERFORMANCE START DATE: 03/12/2006

PERIOD OF PERFORMANCE END DATE: 02/28/2007

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