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DEVELOPMENT OF THE HTS ASSAY FOR E. COLI RNA POLYMERASE

Award Number: R03MH076325
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/15/2005
PERIOD OF PERFORMANCE END DATE: 09/14/2006

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DEVELOPMENT OF THE HTS ASSAY FOR E. COLI RNA POLYMERASE - DESCRIPTION (provided by applicant): RNA polymerase (RNAP) is the principal enzyme of gene expression and the target for genetic regulation. It has been a proven target for antimicrobial therapy, and its mutations are central to the problem of multi-drug resistant (MDR) TB. The long-term objective of this research is the development of interventions in gene expression using small compounds that specifically interfere with the RNAP's catalytic function or its interaction with cellular regulatory factors. For search of RNAP inhibitors we have designed the assay for automated high throughput screening (HTS) of large libraries of chemical compounds. The proposed assay utilizes nucleotide substrate analogs carrying a fluorescent group, which is activated upon release in the polymerization reaction. The assay has been optimized in respect to concentration of the components, reaction conditions and adapted for HTS. The feasibility of the assay has been demonstrated by retrieving of RNAP inhibitors from the collection of 16,000 compounds in HTS setup. The follow-up assays have been developed to detect false positives identified in the primary assay. Experiments are proposed to further increase the assay performance by miniaturization and introduction of the additional follow-up assay to screen out the compounds that target template DNA rather than RNAP. The methodology would be useful for identification of new inhibitors of RNAP suitable for anti-microbial therapy particularly in overcoming the MDR problem. It will also open new approaches to discovery of drugs targeted to specific genes and regulatory pathways. In addition, new inhibitors of RNAP would serve as a potent tool for understanding of the fine mechanisms of RNA synthesis and its regulation.


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: 2005 ( Subtotal = $4,668 )
2005	2005	PUBLIC HEALTH RESEARCH INSTITUTE OF NEW YORK CITY	225 WARREN STREET, SUITE E230F	NEWARK	NJ	07103	ESSEX	USA	Mental Health Research Grants	000	1	9/15/2005	NEW	$4,668
														Subtotal = $4,668

Grand Total All Awards = $4,668

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DEVELOPMENT OF THE HTS ASSAY FOR E. COLI RNA POLYMERASE

Award Number: R03MH076325

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/15/2005

PERIOD OF PERFORMANCE END DATE: 09/14/2006

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