Novel Therapeutics for Heart Failure: Modified, Water-Soluble Caveolin-1 Scaffolding Domain Peptides with Improved Characteristics for Drug Development

心力衰竭的新型疗法：修饰的水溶性 Caveolin-1 支架结构域肽，具有改进的药物开发特性

• 批准号: 10599654
• 负责人: STANLEY R HOFFMAN
• 金额: $ 30万
• 依托单位: FIBROTHERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-15 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10599654
• 关键词: Active Sites; Address; Adult; Affect; Age; Aging; Amino Acids; Angiotensin II; Biological; Biological Models; Blood Vessels; Body Weight; Catheters; Cells; Characteristics; Collagen; Dependence; Deposition; Detection; Development; Diagnosis; Disease; Dose; EFRAC; Echocardiography; Enzymes; Excretory function; Extravasation; Fibrosis; Future; Heart; Heart Diseases; Heart Hypertrophy; Heart failure; High Pressure Liquid Chromatography; Immunoglobulin G; In Vitro; Infusion procedures; Isoproterenol; Lead; Length; Lung diseases; Maximum Tolerated Dose; Medical Care Costs; Metabolism; Methods; Modeling; Modification; Mus; Occupations; Pathologic; Patients; Peptides; Pharmacology; Phosphotransferases; Population; Prevalence; Production; Property; Protein Tyrosine Kinase; Proteolysis; Pulmonary Fibrosis; Regulation; Relaxation; Safety; Shortening Fraction; Side; Specificity; Tertiary Protein Structure; Testing; Therapeutic; Therapeutic Index; Time; Tissues; Toxic effect; Toxicology; Ventricular Function; Water; Weight; absorption; aged; aorta constriction; caveolin 1; coronary fibrosis; design; drug development; efficacy evaluation; experimental study; improved; in vivo; lifetime risk; mortality; mouse model; novel; novel lead compound; novel therapeutics; pharmacologic; phase 2 study; pressure; prophylactic; scaffold; success; therapeutic target; uptake

Abstract Our long-term objective is to fill the unmet need for treatments for heart failure (HF). Caveolin-1 is a promising therapeutic target in fibrotic diseases. The profibrotic effects of caveolin-1 deficiency in cells and in mouse models is suppressed by a peptide equivalent to its active site (caveolin-1 scaffolding domain, CSD). We have shown the beneficial effects of CSD in two independent models of PO-induced cardiac disease [transverse aortic constriction (TAC) and angiotensin II (AngII) infusion] and also in aged mice. In all these models, CSD almost completely suppressed pathological alterations in ventricular function, fibrosis, and microvascular leakage. However, CSD lacks suitable pharmacologic properties for drug development. To address this issue, we developed novel, modified versions of CSD. We first divided CSD into three subregions (amino acids 82- 89, 88-95, 94-101) and found they all suppressed fibrotic disease in vivo. To improve their pharmacology, we modified CSD and each subregion to be water soluble and protected from proteolysis. This modification also enhanced their uptake by cells and increased their ability to inhibit several purified kinases in vitro. So far, we have only had the opportunity to test the modified, water-soluble version of 82-89 (W82-89) in an HF model. W82-89 would be an excellent Lead Compound based on its effects on cardiac hypertrophy, fibrosis, and microvascular leakage. However, because of the distinct pharmacological properties of our four modified peptides, it is quite possible that another peptide is more effective than W82-89. Thus, to select a Lead Compound, we will perform a side-by-side comparison of the four candidates. We will then determine the Therapeutic Index (ratio between toxic and beneficial doses) of the Lead Compound. Specifically, we will: 1) Select a Lead Compound using two model systems: AngII- and Isoproterenol-Induced HF. AngII and isoproter- enol infusion are two frequently used, mechanistically distinct, model systems for inducing HF in mice. Studies will be performed both in a prophylactic and in a therapeutic format (i.e. treatment begins only after disease is established). We will consider these studies to be a success if a Lead Compound is selected that suppresses the pathological effects of AngII and isoproterenol on ventricular function (Ejection Fraction [EF], fractional shortening [FS], isovolumic relaxation time [IVRT]) and cardiac hypertrophy [heart weight/body weight ratio] by >50% and the effects on fibrosis and microvascular leakage by >75%. 2) Determine the Therapeutic Index of the Lead Compound. The dose-dependence of the Lead Compound’s beneficial effects will be determined using doses above and below our current standard dose. Its toxicity will be evaluated in a Single-Treatment Maximum Tolerated Dose Experiment using 1X, 5X, 25X, and 125X our current standard dose. We will consider these studies to be a success if the Therapeutic Index is >50. In summary, these studies will provide a novel Lead Compound that meets our Criteria for Success, both in terms of suppression of HF and of safety.

摘要 我们的长期目标是填补心力衰竭（HF）治疗的未满足需求。Caveolin-1是一个很有前途的 纤维化疾病的治疗靶点。小窝蛋白-1缺乏在细胞和小鼠中的促纤维化作用 模型被与其活性位点（小窝蛋白-1支架结构域，CSD）等同的肽抑制。我们有 显示CSD在PO诱导的心脏病的两个独立模型中的有益作用[横向 主动脉缩窄（TAC）和血管紧张素II（AngII）输注]以及老年小鼠。在所有这些模型中，CSD 几乎完全抑制了心室功能、纤维化和微血管的病理改变 泄漏然而，CSD缺乏用于药物开发的合适的药理学性质。为了解决这个问题， 我们开发了新的CSD的修改版本。我们首先将CSD分为三个亚区（氨基酸82- 88）， 89，88-95，94-101），并发现它们都在体内抑制纤维化疾病。为了改善其药理学，我们 修饰的CSD和每个亚区是水溶性的，并保护免于蛋白水解。该修改还 增强了细胞对它们的摄取，并增加了它们在体外抑制几种纯化激酶的能力。目前为止我们 仅有机会在HF模型中测试82-89（W82-89）的改性水溶性版本。 W82-89将是一个很好的先导化合物，基于其对心脏肥大，纤维化， 微血管渗漏然而，由于我们的四种修饰的不同药理学性质， 因此，很可能另一种肽比W82-89更有效。因此，要选择一个铅 复合，我们将执行并排比较的四个候选人。然后我们将确定 先导化合物的治疗指数（毒性和有益剂量之间的比率）。具体而言，我们将：1） 使用两种模型系统选择先导化合物：AngII和异丙肾上腺素诱导的HF。AngII和isoproter- 烯醇输注是用于在小鼠中诱导HF的两种常用的、机制上不同的模型系统。研究 将以预防和治疗的形式进行（即，治疗仅在疾病发生后开始）。 建立）。如果选择的先导化合物能够抑制 AngII和异丙肾上腺素对心室功能的病理影响（射血分数[EF]，分数 缩短[FS]，等容舒张时间[IVRT]）和心脏肥大[心脏重量/体重比]， >50%，对纤维化和微血管渗漏的影响> 75%。2)治疗指数的确定 铅化合物。将确定先导化合物有益作用的剂量依赖性 使用高于和低于我们目前标准剂量的剂量。其毒性将在单次治疗中进行评价 使用1X、5X、25 X和125 X当前标准剂量的最大耐受剂量实验。我们将 如果治疗指数>50，则认为这些研究成功。总之，这些研究将提供 一种新型先导化合物，在抑制HF和安全性方面均符合我们的成功标准。