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Screening of glucocorticoid receptor small-molecule regulators using cognate…

Award Information

Agency:
Department of Health and Human Services
Branch:
N/A
Award ID:
93420
Program Year/Program:
2009 / SBIR
Agency Tracking Number:
AI082862
Solicitation Year:
N/A
Solicitation Topic Code:
N/A
Solicitation Number:
N/A
Small Business Information
VISTAMOTIF LLC
34E UNIVERSITY HOUSES MADISON, WI 53705
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Woman-Owned: No
Minority-Owned: No
HUBZone-Owned: No
 
Phase 1
Fiscal Year: 2009
Title: Screening of glucocorticoid receptor small-molecule regulators using cognate site
Agency: HHS
Contract: 1R43AI082862-01
Award Amount: $181,875.00
 

Abstract:

DESCRIPTION (provided by applicant): Glucocorticoid receptor (GR) is a member of the nuclear receptor (NR) superfamily that is instrumental in regulating genes involved in inflammation and immunosuppression and represents a major therapeutic target for ast hma, arthritis, lupus, and other chronic disorders. A major challenge in GR drug design is the necessity to enhance GR-mediated anti-inflammatory and immunosuppressive action, while down-regulating deleterious corticosteroid side effects including diabetes , weight gain, hypertension, and osteoporosis. The most critical interaction for GR-mediated gene transcription occurs at its glucocorticoid response element (GRE) DNA site. Variations of the GRE dictate differential gene transcription, yet a comprehensive analysis of GR interaction exploring every permutation of the GRE has not been done. We have developed Cognate Site Identifier (CSI) DNA microarrays containing every permutation of a 12 base pair DNA sequence within duplex DNA. Our proposal will focus on understanding how interactions with ligands and heterodimeric proteins affect GR recognition of DNA, expanding the CSI technology for discovery of novel targets for drug design, small-molecule screening, and development of artificial transcription factors. The specific aims of this Phase I proposal are: 1. DNA binding preferences of GR in response to receptor interactions with ligand and with a heterodimeric partner AP-1 will be characterized using CSI analysis. These studies will identify potential new dru g targets and key changes in DNA binding specificity. 2. DNA-binding small-molecule polyamides, comprised of N-methylpyrrole and N-methylimidazole pairs that can precisely target DNA sites, will be designed to disrupt GR-GRE and GR-AP1-DNA interactions. Th ese molecules will be useful as therapeutics to down-regulate GR-mediated transcription at corticosteroid-regulated genes involved in negative side effects. 3. A high throughput screening platform using CSI microarrays to differentiate test compounds as di sruptors or enhancers of GR-GRE interactions and GR-AP1 binding at composite sites will be developed. In this proposal, we develop a microarray platform to examine the DNA binding specificity of important drug targets for anti-inflammatory therapeutic deve lopment. Targeted effectors of protein-DNA interactions and DNA-mediated allosteric effects on protein-ligand interactions are under-studied areas of drug design that have enormous therapeutic potential. CSI information from GR-DNA interactions will be use d to meaningfully annotate the human genome, to identify differences due to critical single nucleotide polymorphisms in patient populations, and to predict whether a drug target may affect undesirable genes or pathways. The CSI methodology can be applied f or any DNA-binding proteins and molecules, many of which are linked to cancer, diabetes, obesity and other disorders. PUBLIC HEALTH RELEVANCE: A major challenge in glucocorticoid receptor (GR) drug design is the necessity to identify dissociated ligands that enhance anti-inflammatory and immunosuppressive action for treatment of asthma, arthritis, lupus and other disorders, while down-regulating corticosteroid-mediated deleterious side effects such as weight gain, diabetes, hypertension, and osteoporosis. The most critical interaction for GR-mediated gene transcription occurs at its glucocorticoid response element (GRE) DNA site. Variations of the GRE dictate differential gene transcription, yet a comprehensive analysis of GR interaction exploring every pe rmutation of the GRE has not been done. Using Cognate Site Identifier (CSI) DNA microarrays displaying every permutation of a 12 base pair DNA sequence, our proposal will focus on understanding how interactions with ligands and heterodimeric proteins affec t GR recognition of DNA for discovery of novel targets for drug design, small-molecule screening, and development of directed transcription factors.

Principal Investigator:

Christopher L. Warren

Business Contact:

Aseem X. Ansari
Small Business Information at Submission:

VISTAMOTIF LLC
34E UNIVERSITY HOUSES MADISON, WI 53705

EIN/Tax ID: 144390413
DUNS: N/A
Number of Employees: N/A
Woman-Owned: No
Minority-Owned: No
HUBZone-Owned: No