Novel Modulators of LDL Metabolism

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 2R44HL096167-02A1
Agency Tracking Number: R44HL096167
Amount: $1,000,000.00
Phase: Phase II
Program: SBIR
Solicitation Topic Code: NHLBI
Solicitation Number: PA13-088
Timeline
Solicitation Year: 2014
Award Year: 2014
Award Start Date (Proposal Award Date): 2014-08-01
Award End Date (Contract End Date): 2017-04-30
Small Business Information
1 GREAT VALLEY PKY, STE 8, Malvern, PA, 19355-1423
DUNS: 192526221
HUBZone Owned: N
Woman Owned: N
Socially and Economically Disadvantaged: N
Principal Investigator
 NABIL ELSHOURBAGY
 (610) 400-1243
 nabil.elshourbagy@shifabiomedical.com
Business Contact
 SHERIN ABDELMEGUID
Phone: (610) 400-1243
Email: sherin@shifabiomedical.com
Research Institution
N/A
Abstract
DESCRIPTION provided by applicant Heart disease is the leading cause of death for both men and women in the US accounting for nearly of all annual deaths A high cholesterol level is well known risk factors for heart disease Although blood cholesterol can be lowered using a number of marketed drugs of which statins are the leading drugs only of patients taking these drugs are achieving the low density lipoprotein cholesterol goals set by the National Cholesterol Education Program NCEP Furthermore patients with homozygous familial hypercholesterolemia who have markedly elevated cholesterol levels respond poorly to current drug therapy and are at very high risk of premature cardiovascular disease These and other patients will dramatically benefit from an aggressive treatment of hypercholesterolemia The long term goal of this work is to develop novel drugs for cholesterol lowering Our therapeutic target is the protease proprotein convertase subtilisin like kexin type PCSK PCSK controls the degradation of the LDL receptor LDLR in the liver and thereby contributes to cholesterol homeostasis PCSK is synthesized as a precursor protein that undergoes processing between the prodomain and catalytic domain This processing is required for PCSK to be secreted and to undertake its biological activity The secreted enzyme is known to bind to the epidermal growth factor like repeat A EGF A domain of the LDLR Our goal is to identify compounds that interfere with PCSK and the LDLR binding and its ability to participate in the degradation of the LDL receptor To achieve our goal we have integrated virtual computer screening methods and cell based assays and identified screening hits Daily administration of one of these compounds to animals that are fed high fat high cholesterol diet showed significant reduction in cholesterol level As part of Phase II proposal we plan to expand and optimize our hits and confirm the ability of the selected compounds to prevent the LDL receptor degradation and therefore decrease the LDL C level using in vivo studies PUBLIC HEALTH RELEVANCE Heart disease is the leading cause of death for both men and women in the US A high cholesterol level is a well known risk factor for heart disease Although blood cholesterol can be lowered using a number of marketed drugs these drugs do not treat a segment of the population with very high cholesterol Our goal is to develop new cholesterol lowering drugs that have an effect on all individuals with high cholesterol levels including that segment of the population having very high cholesterol levels

* Information listed above is at the time of submission. *

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