USA flag logo/image

An Official Website of the United States Government

Screen for MURF-1 inhibitors to treat myopathy

Award Information

Agency:
Department of Health and Human Services
Branch:
N/A
Award ID:
75843
Program Year/Program:
2005 / SBIR
Agency Tracking Number:
AG025726
Solicitation Year:
N/A
Solicitation Topic Code:
N/A
Solicitation Number:
N/A
Small Business Information
PROGENRA, INC.
271A GREAT VALLEY PKWY 271A GREAT VALLEY PKWY MALVERN, PA 19355-
View profile »
Woman-Owned: No
Minority-Owned: No
HUBZone-Owned: No
 
Phase 1
Fiscal Year: 2005
Title: Screen for MURF-1 inhibitors to treat myopathy
Agency: HHS
Contract: 1R43AG025726-01
Award Amount: $266,848.00
 

Abstract:

DESCRIPTION (provided by applicant): Myopathy (muscle atrophy, or muscle wasting) is a serious clinical complication of cancer, HIV/AIDS, diabetes, and other chronic diseases, leading to increased morbidity and reduced life expectancy. While symptoms have been addressed by a number of interventions, no successful therapy has been developed. Recently, various proteins whose expression is enhanced under conditions of atrophy-inducing starvation have been identified in rats. In particular, the expression of a set of novel genes called atrogins (atrophyspecific genes) increases significantly in skeletal muscles of fasting organisms and decreases rapidly when feeding is resumed. The product of one of these genes - MURF-1 - is RING-finger domain ubiquitin E3 ligase, a critical enzyme of the ubiquitin-proteasomal degradation pathway. Genetic knockout and pharmacological studies have implicated this pathway in muscle atrophy. Thus, attenuation of proteasomal activity associated with muscle wasting may be achievable using inhibitors of MURF-1. In Phase I, E3 ubiquitination activity of MURF-1 will be demonstrated against an appropriate substrate. Then, a yeastbased assay for inhibitors of MURF-1 will be developed and validated, and a collection of natural products extracts will be screened. For the assay, the following will be cloned and expressed in yeast S. cerevisiae: the substrate of MURF-1, fused to p53 linked to a (3-galactosidase reporter; free MURF-1 (E3 ligase); an E3 ligase suitable as a selectivity control. After the assay is adapted to multiwell plates and to parameters acceptable for high throughput screening, a collection of natural product extracts and a set of screening compounds from the NCI will be screened for inhibitors of MURF-1. Successful completion of Phase I should result in at least one extract lead with reasonable potency (IC50 1-5 ug/ml). In Phase II, active principles will be isolated from the best extract leads and best hits from the small molecule screen will be selected for lead optimization, with the goal of identifying novel, potent, and selective inhibitors of MURF-1 for development as therapies for muscle wasting associated with various pathological states.

Principal Investigator:

Michael R. Mattern
6106446974
mattern@progenra.com

Business Contact:

Tauseef Butt
6106446974
BUTT@PROGENRA.COM
Small Business Information at Submission:

Progenra, Inc.
271 Great Valley Parkway, Suite 300 Malvern, PA 19355

EIN/Tax ID: 061660578
DUNS: N/A
Number of Employees: N/A
Woman-Owned: No
Minority-Owned: No
HUBZone-Owned: No