Development of Modified Caveolin-1 Scaffolding Domain Peptides with Improved Pharmacological Properties as Therapeutic Agents for Scleroderma Skin Disease

开发具有改善药理特性的修饰的 Caveolin-1 支架结构域肽作为硬皮病皮肤病的治疗剂

基本信息

  • 批准号:
    10544238
  • 负责人:
  • 金额:
    $ 25.96万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-09-01 至 2024-08-31
  • 项目状态:
    已结题

项目摘要

Abstract Our long-term objective is to develop an effective treatment for scleroderma (systemic sclerosis, SSc) skin fibrosis. 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). However, CSD lacks suitable pharmacologic properties for drug development. To overcome this problem, we developed novel, modified versions of CSD. We first divided CSD into three subregions and found that all three suppressed bleomycin-induced skin fibrosis. To improve, the pharmacological properties, we then modified CSD and each subregion to be water soluble and protected from proteolysis. This modification greatly enhanced the uptake by cells of all four modified peptides and also greatly increased their ability to inhibit several purified kinases in vitro. We have so far tested only one of the four modified peptides in vivo and it was outstandingly active in inhibiting bleomycin-induced dermal fibrosis as well as the associated loss of the intradermal adipose layer (lipoatrophy). These initial studies justify and outstandingly support our proposal to identify a Lead Compound from among the four candidates, then evaluate its Therapeutic Index (ratio between toxic and beneficial doses). Our studies and the literature also suggest that our peptides will be more effective and have fewer side effects than the blockbuster FDA- approved drug pirfenidone (brand name Esbriet). In summary, to proceed with drug development we must identify a Lead Compound. Due to their distinct pharmacological and functional differences, we must do a side- by-side comparison of our four modified peptides. 1) Select a Lead Compound using two model systems: Systemic Bleomycin Treatment and Subcutaneous TGFβ Injection. We will identify a Lead Compound, then demonstrate its specificity and activity by comparing it to a control peptide (scrambled Lead) and to nintedanib. Peptides will be delivered s.c. in a Therapeutic Protocol, beginning one week after fibrosis is induced. Primary Readouts will be dermal fibrosis and lipoatrophy. Secondary Readouts will be the levels of markers for myofibroblasts, adipocytes, and inflammatory cells. Success will be defined as >50% reversal of the deleterious effects of bleomycin and TGFβ on the Primary and Secondary Readouts. 2) Determine the Therapeutic Index of the Lead Compound. The dose-dependence of the beneficial effects of the Lead Compound will be determined using doses above and below our current standard dose. The toxicity of the Lead Compound will be evaluated in a Single-Treatment Maximum Tolerated Dose (MTD) 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 skin disease and of safety.
摘要我们的长期目标是开发一种治疗硬皮病(系统性硬化症, SSC)皮肤纤维化。小窝蛋白-1是治疗纤维化疾病的一个有前景的靶点。阿司匹林的促肝纤维化作用 细胞和小鼠模型中的小窝蛋白-1缺乏症可被相当于其活性部位的多肽抑制 (Caveolin-1支架结构域,CSD)。然而,CSD缺乏合适的药物药理性质 发展。为了克服这个问题,我们开发了CSD的新的修改版本。我们首先划分了CSD 分成三个亚区,发现三个亚区都能抑制博莱霉素诱导的皮肤纤维化。为了改进, 药理特性,然后我们修改了CSD和每个分区,使其具有水溶性并防止 蛋白质分解。这种修饰极大地提高了细胞对所有四种修饰多肽的摄取,还 极大地提高了它们在体外对几种纯化的激酶的抑制能力。到目前为止,我们只测试了其中一种 四个修饰多肽在体内,并具有显著的抑制博莱霉素诱导的皮肤纤维化的活性 以及伴随的真皮内脂肪层的丢失(脂肪萎缩)。这些初步研究证明了 突出地支持我们的建议,从四个候选者中确定一个先导化合物,那么 评估其治疗指数(毒性剂量与有益剂量之比)。我们的学习和文学也 表明我们的多肽将比畅销的FDA更有效,副作用更少- 批准的药物吡非尼酮(商标为Esbriet)。总而言之,要继续药物开发,我们必须 确定一种先导化合物。由于它们在药理和功能上的明显差异,我们必须做一个侧面- 对我们的四种修饰多肽进行了比对。1)使用两个模型系统选择一种铅化合物: 全身博莱霉素联合转化生长因子β皮下注射。我们将确定一种先导化合物,然后 通过将其与对照多肽(混杂铅)和九替达尼进行比较,证明其特异性和活性。 多肽将被送到S.C.在治疗方案中,从诱导纤维化一周后开始。主要 读数将是真皮纤维化和脂肪萎缩。二级读数将是以下各项的标记级别 肌成纤维细胞、脂肪细胞和炎性细胞。成功将定义为>50%的 博莱霉素和转化生长因子β对一、二次读数的影响2)确定 先导化合物的治疗指数。铅有益效应的剂量依赖性 将使用高于和低于我们当前标准剂量的剂量来确定化合物。它的毒性 铅化合物将在一次治疗最大耐受量(MTD)实验中进行评估,使用 我们当前标准剂量的1X、5X、25X和125X。我们将认为这些研究是成功的,如果 治疗指数为>50。总而言之,这些研究将提供一种新的先导化合物,符合我们的 成功的标准,无论是在皮肤病的抑制和安全性方面。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

STANLEY R HOFFMAN其他文献

STANLEY R HOFFMAN的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('STANLEY R HOFFMAN', 18)}}的其他基金

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
  • 财政年份:
    2023
  • 资助金额:
    $ 25.96万
  • 项目类别:
Novel Therapeutics for Interstitial Lung Disease: Modified, Water-Soluble Caveolin-1 Scaffolding Domain Peptides with Improved Characteristics for Drug Development
间质性肺疾病的新疗法: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:
    10544228
  • 财政年份:
    2022
  • 资助金额:
    $ 25.96万
  • 项目类别:
Curcumin Treatment of Lung Fibrosis: Improved Delivery and Target Cells
姜黄素治疗肺纤维化:改善递送和靶细胞
  • 批准号:
    7789215
  • 财政年份:
    2010
  • 资助金额:
    $ 25.96万
  • 项目类别:
Curcumin Treatment of Lung Fibrosis: Improved Delivery and Target Cells
姜黄素治疗肺纤维化:改善递送和靶细胞
  • 批准号:
    8062291
  • 财政年份:
    2010
  • 资助金额:
    $ 25.96万
  • 项目类别:
PKCepsilon-Related Proteins in Lung Fibrosis
肺纤维化中的 PKCepsilon 相关蛋白
  • 批准号:
    7108637
  • 财政年份:
    2003
  • 资助金额:
    $ 25.96万
  • 项目类别:
PKCepsilon-Related Proteins in Lung Fibrosis
肺纤维化中的 PKCepsilon 相关蛋白
  • 批准号:
    6663559
  • 财政年份:
    2003
  • 资助金额:
    $ 25.96万
  • 项目类别:
PKCepsilon-Related Proteins in Lung Fibrosis
肺纤维化中的 PKCepsilon 相关蛋白
  • 批准号:
    6922076
  • 财政年份:
    2003
  • 资助金额:
    $ 25.96万
  • 项目类别:
PKCepsilon-Related Proteins in Lung Fibrosis
肺纤维化中的 PKCepsilon 相关蛋白
  • 批准号:
    6793607
  • 财政年份:
    2003
  • 资助金额:
    $ 25.96万
  • 项目类别:
R21 Project: Curcumin Treatment of Fibrosis
R21项目:姜黄素治疗纤维化
  • 批准号:
    6512087
  • 财政年份:
    2001
  • 资助金额:
    $ 25.96万
  • 项目类别:
Curcumin Treatment of Fibrosis
姜黄素治疗纤维化
  • 批准号:
    6371149
  • 财政年份:
    2001
  • 资助金额:
    $ 25.96万
  • 项目类别:

相似国自然基金

相似海外基金

Recruitment of brown adipocytes in visceral white adipose tissue by fibroblast growth factor 8b
成纤维细胞生长因子 8b 将棕色脂肪细胞募集到内脏白色脂肪组织中
  • 批准号:
    321208980
  • 财政年份:
    2016
  • 资助金额:
    $ 25.96万
  • 项目类别:
    Research Grants
Enhancing Energy Expending Adipocytes in White Adipose Tissue
增强白色脂肪组织中的能量消耗脂肪细胞
  • 批准号:
    8827438
  • 财政年份:
    2014
  • 资助金额:
    $ 25.96万
  • 项目类别:
Induction of brown-like adipocytes in white adipose tissue by food-derived factors
食物源性因子在白色脂肪组织中诱导棕色样脂肪细胞
  • 批准号:
    26450168
  • 财政年份:
    2014
  • 资助金额:
    $ 25.96万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
WAT-on-a-chip - Development of a micofluidic, microphysiologic in vitro adipose tissue model for high-throughput drug screening based on hiPSC-derived adipocytes.
WAT-on-a-chip - 开发微流体、微生理体外脂肪组织模型,用于基于 hiPSC 衍生脂肪细胞的高通量药物筛选。
  • 批准号:
    257256526
  • 财政年份:
    2014
  • 资助金额:
    $ 25.96万
  • 项目类别:
    Research Fellowships
Enhancing Energy Expending Adipocytes in White Adipose Tissue
增强白色脂肪组织中的能量消耗脂肪细胞
  • 批准号:
    8828181
  • 财政年份:
    2013
  • 资助金额:
    $ 25.96万
  • 项目类别:
Enhancing Energy Expending Adipocytes in White Adipose Tissue
增强白色脂肪组织中的能量消耗脂肪细胞
  • 批准号:
    8520690
  • 财政年份:
    2013
  • 资助金额:
    $ 25.96万
  • 项目类别:
Enhancing Energy Expending Adipocytes in White Adipose Tissue
增强白色脂肪组织中的能量消耗脂肪细胞
  • 批准号:
    8629741
  • 财政年份:
    2013
  • 资助金额:
    $ 25.96万
  • 项目类别:
Effect of exercise training on formation of brite adipocytes within white adipose tissue
运动训练对白色脂肪组织内脂肪细胞形成的影响
  • 批准号:
    23700778
  • 财政年份:
    2011
  • 资助金额:
    $ 25.96万
  • 项目类别:
    Grant-in-Aid for Young Scientists (B)
Investigation for the mechanisms of the emergence of brown adipocytes in white adipose tissue
白色脂肪组织中棕色脂肪细胞出现机制的研究
  • 批准号:
    21780261
  • 财政年份:
    2009
  • 资助金额:
    $ 25.96万
  • 项目类别:
    Grant-in-Aid for Young Scientists (B)
LOUISIANA COBRE: P1: INDUCE THERMOGENIC BROWN ADIPOCYTES IN WHITE ADIPOSE TISSUE
路易斯安那 COBRE:P1:在白色脂肪组织中诱导产热棕色脂肪细胞
  • 批准号:
    7610781
  • 财政年份:
    2007
  • 资助金额:
    $ 25.96万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了