Small molecule allosteric inhibitors of PCSK9 processing to phenocopy cardioprotective genetic variants.

PCSK9 处理表型心脏保护性遗传变异的小分子变构抑制剂。

• 批准号: 10747623
• 负责人: John S Chorba
• 金额: $ 53.75万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10747623
• 关键词: Acceleration; Affect; Alleles; Antibodies; Arterial Fatty Streak; Atherosclerosis; Biological Assay; Cardiovascular Diseases; Cardiovascular system; Cells; Chemicals; Clinical; Coronary heart disease; Development; Disease; Diversity Library; Drug Targeting; Evaluation; Exhibits; Genetic Models; Goals; Government; Health Services Accessibility; Heart Diseases; Hepatic; Human; Human Genetics; Impairment; Improve Access; Inflammatory; Injections; Insurance; Insurance Carriers; Intellectual Property; Knowledge; LDL Cholesterol Lipoproteins; Lead; Legal patent; Libraries; Literature; Liver; Liver Circulation; Liver diseases; Low Density Lipoprotein Receptor; Low-Density Lipoproteins; Luciferases; Lysosomes; Molecular; Molecular Chaperones; Mus; Mutation; Oral; Outcome; Patients; Peptide Hydrolases; Persons; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Phenocopy; Phenotype; Preclinical Testing; Production; Property; Proteins; Proteolysis; Recombinants; Regulation; Risk Factors; Role; Safety; Series; Serum; Site; Small Interfering RNA; Solubility; Substrate Specificity; Surface; Testing; Therapeutic; Toxic effect; Validation; Variant; analog; biophysical analysis; cardioprotection; cost; efficacy evaluation; genetic variant; high throughput screening; improved; in vivo; in vivo Model; inhibitor; interest; novel; overexpression; pharmacologic; pre-clinical; preclinical development; scaffold; side effect; small molecule; small molecule inhibitor; small molecule therapeutics; success

PROJECT SUMMARY/ABSTRACT The self-cleaving protease PCSK9 induces the lysosomal degradation of the hepatic low-density lipoprotein receptor (LDLR). Thus, PCSK9 raises serum LDL and promotes atherosclerotic heart disease. Human genetics show that secreted PCSK9 is dispensable, making PCSK9 an important drug target. Both therapeutic anti-PCSK9 antibodies and liver-specific anti-PCSK9 siRNA impressively lower LDL and improve cardiovascular outcomes, even when added on top of statins. Yet despite this clinical success, problems remain. First, the role of PCSK9 beyond downregulating the hepatic LDLR remains unclear, and so there are gaps in the knowledge of the site effects from or other indications for the current available therapies. Second, currently approved therapies are not orally available, expensive, and poorly covered by insurance (antibodies), or phenocopy genetic models that associate with liver disease (siRNA). In this proposal, we target a novel mechanism for PCSK9 inhibition: the disruption of PCSK9 processing. PCSK9 is a self-cleaving protease, and this auto-proteolysis is required for its secretion and full effect on the LDLR. However, because PCSK9’s cleavage is both intramolecular and terminal, no other group has discovered how to disrupt it. Our group, however, has solved this problem, and we have discovered a series of molecules that allosterically modulate PCSK9 proteolysis to disrupt PCSK9 function. Importantly, this mechanism phenocopies the well-tolerated human PCSK9 variants who have no adverse phenotypes, only lower LDL and cardiovascular protection. In the R61 phase of this proposal, we will pursue a medicinal chemistry campaign to identify, validate, and screen compounds for activity. We will generate a diversity library to establish novel intellectual property, confirm target engagement with PCSK9, and improve the efficacy, potency, and pharmacologic properties of our compounds. In the R33 phase, we will establish in vivo efficacy and pharmacologically validate a developmental candidate to identify a lead compound for IND-enabling studies. We anticipate that our proposal will have a high impact on cardiovascular disease by enabling the development of an oral small molecule inhibitor of PCSK9 that truly phenocopies the cardioprotective genetic variants found in humans.

项目总结/摘要 自切割蛋白酶PCSK 9诱导肝脏低密度脂蛋白的溶酶体降解 受体（LDLR）。因此，PCSK 9升高血清LDL并促进动脉粥样硬化性心脏病。人类 遗传学表明，分泌的PCSK 9是不稳定的，使PCSK 9成为重要的药物靶标。治疗性 抗PCSK 9抗体和肝脏特异性抗PCSK 9 siRNA显著降低LDL， 心血管结局，即使在他汀类药物的基础上添加。然而，尽管临床上取得了成功， 保持。首先，PCSK 9除了下调肝脏LDLR之外的作用仍不清楚，因此存在以下问题： 对当前可用疗法的部位效应或其他适应症的了解存在差距。第二、 目前批准的疗法不能口服、昂贵，并且保险（抗体）覆盖不足， 或与肝病相关的表型遗传模型（siRNA）。 在这项提案中，我们针对PCSK 9抑制的一种新机制：PCSK 9加工的中断。 PCSK 9是一种自切割蛋白酶，这种自蛋白水解是其分泌和对细胞的完全作用所必需的。 LDLR。然而，由于PCSK 9的切割是分子内和末端的，没有其他基团具有 然而，我们的团队已经解决了这个问题，我们发现了一系列 变构调节PCSK 9蛋白水解以破坏PCSK 9功能的分子。重要的是这 机制表型模仿耐受良好的人PCSK 9变体，这些变体没有不良表型， 降低LDL和心血管保护。在本提案的R61阶段，我们将寻求一种药物， 化学活动，以确定，验证和筛选化合物的活性。我们将创建一个多样性图书馆 建立新的知识产权，确认与PCSK 9的靶点结合，并提高疗效， 我们的化合物的效力和药理学特性。在R33阶段，我们将确定体内疗效 并对开发候选物进行初步验证，以确定用于IND的先导化合物 问题研究我们预计，我们的提案将对心血管疾病产生重大影响， 开发一种口服小分子PCSK 9抑制剂，真正表型模仿心脏保护基因 在人类身上发现的变种