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.

抽象的 我们的长期目标是满足心力衰竭 (HF) 治疗方面未得到满足的需求，Caveolin-1 是一种很有前景的药物。 Caveolin-1 缺陷对细胞和小鼠的促纤维化作用。 模型被与其活性位点等效的肽（caveolin-1 支架结构域，CSD）抑制。 显示了 CSD 在 PO 诱发的心脏病的两个独立模型中的有益作用 [横 主动脉缩窄（TAC）和血管紧张素II（AngII）输注]以及在所有这些模型中，CSD。 几乎完全抑制心室功能、纤维化和微血管的病理改变 然而，CSD 缺乏适合药物开发的药理学特性。 我们开发了 CSD 的新型改良版本 我们首先将 CSD 分为三个子区域（氨基酸 82-）。 89、88-95、94-101）并发现它们都能抑制体内纤维化疾病。为了改善它们的药理学，我们。 将 CSD 和每个分区修改为水溶性并防止蛋白水解。 增强细胞对它们的摄取并增加它们在体外抑制几种纯化激酶的能力。 我们只有机会在 HF 模型中测试 82-89 (W82-89) 的改良水溶性版本。 基于 W82-89 对心脏肥大、纤维化和心脏功能的影响，W82-89 将是一种出色的先导化合物。 然而，由于我们的四种改良药物具有独特的药理特性。 肽，很可能另一种肽比 W82-89 更有效，因此，选择先导肽。 复合，我们将对四个候选者进行并排比较，然后确定。 先导化合物的治疗指数（有毒剂量与有益剂量之间的比率）具体而言，我们将： 1) 使用两个模型系统选择先导化合物：AngII 和异丙肾上腺素诱导的 HF。 烯醇输注是两种常用的、机制不同的模型系统，用于诱导小鼠心力衰竭研究。 将以预防和治疗的形式进行（即治疗仅在疾病发生后才开始） 如果选择了抑制的先导化合物，我们将认为这些研究是成功的。 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% 且对纤维化和微血管渗漏的影响 >75% 2) 确定治疗指数。 先导化合物的有益效果的剂量依赖性将被确定。 使用高于和低于我们当前标准剂量的剂量将在单一治疗中评估其毒性。 我们将使用当前标准剂量的 1X、5X、25X 和 125X 进行最大耐受剂量实验。 如果治疗指数> 50，则认为这些研究是成功的。 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。