Recent phase II clinical studies demonstrate that an antibody targeting proportion convertase subtilisin/kexin type 9 (PCSK9)-a target for the treatment of hypercholesterolemia and coronary heart disease-successfully and safely decreases amounts of low-density lipoprotein-cholesterol (LDL) in patients with hypercholesterolaemia undertaking statin treatment.1,2 However, to date, there are no reports of small molecules or peptides achieving the same effect. This application offers a mature fragment-based design methodology to create novel small molecule PCSK9 inhibitors that achieve a targeted activity in surface plasmon resonance direct and competition assays as well as in a functional assay, LDL uptake in hepatocyte cells. Such an alternative approach to this problem is compelling because high-throughput screening campaigns at large pharmaceutical companies have generally not yielded progressable hits for PCSK9. Using our recently described hot-spot mapping technique,3,6 we found sites at the low-density lipoprotein-cholesterol receptor (LDLR)/PCSK9 interface that are sites of high interaction energy and appear druggable. Our primary deliverable for the proposed research is to improve physical properties and develop SAR around our initial hits that show functional cell-based activity. The primary hits resulted from testing fewer than 50 novel compounds (one, two and three fragment builds). The small molecule ligands were specifically designed to implement a hypothesis that quantum resonance (partially covalent binding) can provide enhanced affinity to overcome the dehydration costs of the convex, solvent-exposed PCSK9/LDLR interface. Such compounds achieving success in clinical trials would show great promise as a therapeutic to lower cholesterol and treat coronary heart disease in humans.
Public Health Relevance Statement: Public Health Relevance: Phase II clinical trials recently revealed that antibodies-targeting pro-protein convertase subtilisin kexin type-9 (PCSK9)-administered over an 8 to 12 week period significantly reduced bad cholesterol by 50-70% in patients with elevated cholesterol on a stable dose of statins. To date, no small molecule or peptide has been reported that is able to achieve similar results. In this application we aim to employ our fragment-based design methodology to further develop initial hits on PCSK9 into leads with improved affinity and solubility, with a future goal of reaching the antibody performance, and licensing a clinical candidate to a major pharmaceutical company for clinical development.
NIH Spending Category: Biotechnology; Cardiovascular; Heart Disease; Heart Disease - Coronary Heart Disease
Project Terms: Address; Affinity; Algorithms; Antibodies; base; Binding (Molecular Function); Binding Proteins; Biochemical; Biological Assay; Biological Availability; Cells; Charge; Chemicals; Chemistry; Cholesterol; Clinical; Clinical Research; Clinical Trials; Coronary heart disease; cost; Data; Dehydration; design; design and construction; Development; Dihydrofolate Reductase; Dose; Drosophila pros protein; drug discovery; Drug Kinetics; Evaluation; Fluorescence Resonance Energy Transfer; fluoromethyl 2,2-difluoro-1-(trifluoromethyl)vinyl ether; functional group; Future; Goals; Hepatocyte; high throughput screening; Hot Spot; Human; hypercholesterolemia; improved; inhibitor/antagonist; insight; kexin; LDL Cholesterol Lipoproteins; Libraries; Licensing; Ligands; Link; Lipoprotein Receptor; Maps; meetings; Methodology; Methods; molecular dynamics; novel; Outcome; Patients; Peptides; Performance; Pharmacologic Substance; Phase; Phase II Clinical Trials; physical property; primary outcome; Process; programs; Property; Proteins; public health relevance; quantum; Quantum Mechanics; receptor; receptor binding; Renin; Reporting; Research; Running; Simulate; simulation; Site; small molecule; Solubility; Solvents; Stress; Structure; Structure-Activity Relationship; Subtilisins; success; Surface Plasmon Resonance; Techniques; Test Result; Testing; Therapeutic; Triage; uptake; Water
