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Computational Development of Novel Dyslipidemia Therapeutic Candidates to Disrupt ApoC-III Conformation

破坏 ApoC-III 构象的新型血脂异常治疗候选物的计算开发

基本信息

批准号：
10760187
负责人：
Urban A Kiernan
金额：
$ 28.31万
依托单位：
IMETABOLIC BIOPHARMA CORPORATION
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10760187
关键词：
Adhesions Affinity Apolipoprotein E Apolipoproteins B Bacteriophages Binding Biological Biology Blood Vessels Cardiovascular Diseases Cardiovascular system Catabolism Cause of Death Characteristics Cholesterol Circulation Computer Models Developing Countries Development Disease Dyslipidemias Endothelial Cells Engineering Epitopes Evaluation Exhibits Expression Library FDA approved Fluorescence Generations Hepatic High Density Lipoprotein Cholesterol High Density Lipoproteins Image Impairment Industry LDL Cholesterol Lipoproteins Label Libraries Link Lipase Lipids Lipoprotein Binding Lipoproteins Low-Density Lipoproteins Machine Learning Measurable Mediating Molecular Molecular Conformation Mutation Nature Pathology Patients Pharmaceutical Preparations Phase Plasma Play Preclinical Testing Process Proteins Proteoglycan Recombinant Proteins Reporter Research Resistance Role Small Business Innovation Research Grant Structure Testing Therapeutic Therapeutic Effect Therapeutic Intervention Triglycerides United States Work antibody engineering apolipoprotein C-III biological systems cardiovascular risk factor design drug discovery feasibility testing flexibility in silico innovation lipid metabolism lipoprotein lipase monocyte network models novel novel therapeutics particle prevent receptor satisfaction screening therapeutic candidate therapeutic development tool uptake

项目摘要

Project Abstract Cardiovascular Disease (CVD) is a significant threat in the United States and developing countries across the globe. Widely associated with elevated low density lipoprotein cholesterol (LDL-c), therapeutic interventions are primarily focused on reduction of LDL-c plasma levels. Despite the ability to therapeutically reach these target levels, many patients maintain high cardiovascular risk profiles. A causal contributor to this therapeutic paradox is the development of triglyceride-rich lipoprotein (TRL) particles, highly atherogenic remnant particles that are the result of impaired lipase catabolism. Exhibiting resistance to current FDA approved LDL-c lowering medications, these particles maintain significant cardiovascular risk despite the over lowering of LDL-c. It has been determined that high apolipoprotein C-III (ApoC-III) is a hallmark of TRL particles. The sinister nature of ApoC-III is well established as it possesses key functions that include, but are not limited to; inhibition of Lipoprotein Lipase (LPL), impairment of HDL cholesterol efflux and retardation of lipoprotein particle hepatic uptake. As a potential solution, iMBP is developing new therapeutic compounds that target ApoC-III. Our current research efforts have computationally identified the potential to induce a conformational distortion in the ApoC-III target upon binding. Due to a highly flexible hinge region in the molecule that is necessary for ApoC-III to stabilize on lipoprotein particles, the induction of a conformational change could provide a unique therapeutic mode of action in action for reducing TRL levels. This proof-of-concept work is to computationally reengineer a current proprietary therapeutic candidate to augmented ApoC-III distortion capabilities. An expression library will then be expressed and top candidates will be functionally tested for binding. Split into 2 Specific Aims, the final evaluation of feasibility testing will determine the degree of distortion that is achieved as a consequence of binding. The milestone for this final Aim is the identification of a molecule that binds ApoC-III and creates a measurable change in its conformation exhibited as an increase in the protein’s end to end distance. The satisfaction of this milestone would lead to a SBIR Phase 2 plan that would further evaluate the influence that an artificially induced ApoC-III conformational distortion could play in destabilizing its lipoprotein particle binding characteristics and assist in plasma clearance that would culminate in pre-clinical testing.

项目摘要