Novel Modulators of LDL Metabolism

DESCRIPTION (provided by applicant): Heart disease is the leading cause of death for both men and women in the US, accounting for nearly 40% of all annual deaths. 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, of which statins are the leading drugs, only 38% of patients taking these drugs achieve 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 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 interface between the protease proprotein convertase subtilisin-like kexin type 9 (PCSK9) and the low density lipoprotein receptor (LDLR), where we propose to identify and develop compounds that prevent PCSK9 from binding to the LDLR. PCSK9 regulates the degradation of the LDLR in the liver by binding to LDLR on the cell surface, and thereby contributes to cholesterol homeostasis. PCSK9 is made as a zymogen that requires autocatalytic processing for proper secretion; the secreted enzyme is known to bind to the epidermal growth factor-like repeat A (EGF-A) domain of the LDLR. Our attempts to interfere with the interface between PCSK9 and the LDLR will be facilitated by the availability of the crystal structure of the PCSK9/LDLR-EGF-A complex. To achieve our goal, we will integrate virtual (computer) screening methods and in vitro assays to identify lead compounds that can potentially be optimized to produce cholesterol lowering drugs. Virtual screening, which requires the availability of atomic resolution 3D structures of the target protein, provides a cost effective way to screen million of compounds to identify a small set to be purchased and tested in a biological, biophysical or biochemical assay. The specific aims of this work are to: 1. Use virtual screening methods to identify compounds that bind to PCSK9 and block its binding to the LDLR. 2. Use in vitro assays to confirm the ability of the selected compounds to bind to PCSK9 and prevent its binding to the LDLR. 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.