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

• 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
• 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

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 心血管疾病 (CVD) 是美国和发展中国家的重大威胁 在全球范围内与低密度脂蛋白胆固醇（LDL-c）升高广泛相关， 尽管治疗干预主要集中于降低 LDL-c 血浆水平。 尽管无法在治疗上达到这些目标水平，但许多患者仍保持较高的心血管风险 造成这种治疗悖论的一个原因是富含甘油三酯的发展。 脂蛋白（TRL）颗粒，高度致动脉粥样硬化的残余颗粒，是受损的结果 对当前 FDA 批准的 LDL-c 降低药物表现出抗性， 尽管低密度脂蛋白胆固醇过度降低，但这些颗粒仍然存在显着的心血管风险。 已确定高载脂蛋白 C-III (ApoC-III) 是 TRL 颗粒的标志。 ApoC-III 的险恶本质是众所周知的，因为它具有关键功能，包括但不限于 不限于；抑制脂蛋白脂肪酶（LPL）、损害 HDL 胆固醇流出以及 作为一种潜在的解决方案，iMBP 正在开发新的脂蛋白颗粒肝脏摄取。 我们目前的研究工作已经通过计算实现了针对 ApoC-III 的治疗化合物。 确定了结合后 ApoC-III 靶标发生构象扭曲的潜力。 由于分子中具有高度灵活的铰链区，这是 ApoC-III 稳定所必需的 脂蛋白颗粒，构象变化的诱导可以提供独特的治疗 降低 TRL 水平的行动模式这项概念验证工作是通过计算进行的。 重新设计当前专有的治疗候选药物以增强 ApoC-III 畸变 然后将表达一个表达库，并在功能上对最佳候选者进行表达。 进行绑定测试。分为 2 个具体目标，可行性测试的最终评估将确定 由于绑定而达到的扭曲程度是本次决赛的里程碑。 目的是鉴定结合 ApoC-III 的分子，并在其结构中产生可测量的变化。 构象表现为蛋白质端到端距离的增加。 这一里程碑将导致 SBIR 第二阶段计划的实施，该计划将进一步评估 人工诱导的 ApoC-III 构象扭曲可能会破坏其脂蛋白的稳定性 颗粒结合特性并协助血浆清除，最终在临床前达到顶峰 测试。