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。

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要/摘要自切换的蛋白酶pcsk9诱导肝低密度脂蛋白的溶酶体降解受体（LDLR）。这是PCSK9提高血清LDL并促进动脉粥样硬化心脏病。人类遗传学表明，分泌的PCSK9是可分配的，使PCSK9成为重要的药物靶标。两种疗法抗PCSK9抗体和肝特异性抗PCSK9 siRNA令人印象深刻的LDL并改善即使在他汀类药物的顶部添加时，心血管结局也是如此。目的地这个临床成功，问题保持。首先，PCSK9的作用不超出下调Hepatitic LDLR尚不清楚，因此有从现场可用疗法中了解现场影响或其他指示的差距。第二，目前批准的疗法尚未口服，昂贵且被保险覆盖不良（抗体），或与肝病（siRNA）相关的遗传模型。在此提案中，我们针对PCSK9抑制的新型机制：PCSK9处理的破坏。 PCSK9是一种自我切割的蛋白酶，这种自身蛋白酶解体是其分泌所必需的，并且对 ldlr。但是，由于PCSK9的裂解既是分子内和终端，因此没有其他组有发现了如何破坏它。但是，我们的小组解决了这个问题，我们发现了一系列变构调节PCSK9蛋白水解以破坏PCSK9功能的分子。重要的是，这个机制该机制耐受性良好的人PCSK9变体没有不良表型，仅下LDL和心血管保护。在本提案的R61阶段，我们将进行医学化学运动以识别，验证和屏幕化合物进行活动。我们将生成一个多元化库要建立新颖的知识产权，请确认与PCSK9的目标参与，并提高效率，我们化合物的效力和药物特性。在R33阶段，我们将建立体内效率并从物理验证发展候选者以识别铅化合物以辅助研究。我们预计我们的建议将对心血管疾病产生很大的影响开发PCSK9的口服小分子抑制剂，该抑制剂真正表现为心脏保护通用在人类中发现的变体。