Sulfated Polysaccharide Derivatives for the Treatment of Rosacea

用于治疗红斑痤疮的硫酸化多糖衍生物

基本信息

  • 批准号:
    7673060
  • 负责人:
  • 金额:
    $ 14.98万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2009
  • 资助国家:
    美国
  • 起止时间:
    2009-04-24 至 2009-10-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Rosacea is a common disfiguring skin disease affecting 3% of the population over 30 years of age, or 14 million Americans. In men and women of Celtic origin, Rosacea causes central erythema of the face, with highly visible dilated blood vessels and pustules. Dry, itchy eyes are also common. In men, Rosacea can thicken the skin of the nose to create the classical "W.C. Fields" nose, or rhinophyma. The molecular etiology of Rosacea is the cutaneous over-production of cationic anti-microbial peptides cathelicidins and their processing serine proteases. Injection of Rosacea-like concentrations of the 37-amino acid C-terminal cleavage product of hCAP18, termed LL-37, into mouse skin reproduces the redness and polymorphonuclear leukocyte (PMN) infiltration characteristic of the disease. GlycoMira has synthesized several partially lipophilic, sulfated derivatives of a common polysaccharide that show anti-inflammatory activities at nanogram/ml concentrations, including inhibition of the cationic PMN protease human leukocyte elastase (HLE) and inhibition of the PMN adhesion receptor P-selectin. Most importantly, these sulfated and alkylated polysaccharides potently inhibit of the interaction of the receptor for advanced glycation end-products (RAGE) with its many ligands, including carboxy-methyl lysine albumin (CML-BSA), S100 calgranulins, and high mobility box group protein-1 (HMGB- 1). This Phase I project will test the hypothesis that topical application of these proprietary agents can be used as a novel therapy for Rosacea by the dual actions of charge neutralizing and inhibiting the cutaneous inflammatory activity of excess cationic cathelicidins in the skin of patients with this disease. In Aim 1, sixteen analogs will be synthesized and chemically characterized to explore structure-activity space by varying molecular size, sulfation and alkylation. In Aim 2 we will determine the biochemical activities of these compounds as inhibitors of P-selectin, HLE, and interaction of RAGE with four ligands. In Aim 3, we will evaluate the feasibility of using these compounds to prevent LL-37-induced IL-8 secretion by cultured human keratinocytes. Using the two most active compounds from in vitro experiments, in Aim 4 we will demonstrate the feasibility of using these selected active compounds to reduce the local erythema and dermal PMN infiltration in response to subcutaneous injection of LL-37 in mice. Following this feasibility study, GlycoMira will pursue a Phase II project to leverage the development of a topically-applied formulation of our lead drug, demonstrate its efficacy topically in blocking dermal toxicity from intra-dermal LL-37 injection, and complete the pre-clinical toxicology studies to support filing an investigational new drug application. PUBLIC HEALTH RELEVANCE: Rosacea is a common disfiguring skin disease affecting 3% of the U.S. population over 30 years of age, or 14 million Americans. Afflicting primarily Caucasian women of Celtic descent, Rosacea is characterized by erythema of the face with highly visible telangieactatic blood vessels, often with papules and pustules. Rosacea can also produce dry, itchy eyes and, in men, a bulbous thickened nose, or rhinophyma. There is no cure for the disease and its treatment is largely empiric and imperfect. We propose to develop anionic, partially lipophilic hyaluronic acid derivatives as the first mechanistically-based treatment for this chronic, disfiguring skin disorder.
描述(由申请人提供):酒渣鼻是一种常见的毁容皮肤病,影响3%的30岁以上人口,或1400万美国人。在凯尔特血统的男性和女性中,酒渣鼻引起面部的中枢性红斑,伴有高度可见的血管扩张和脓疱。眼睛干燥、发痒也很常见。在男性中,酒糟鼻会使鼻子皮肤变厚,形成典型的“W.C.菲尔兹”鼻,或鼻赘。酒渣鼻的分子病因是皮肤中阳离子抗菌肽cathelicidins及其加工丝氨酸蛋白酶的过量产生。将类似酒渣鼻浓度的37个氨基酸的hCAP18 c端裂解产物(称为LL-37)注射到小鼠皮肤中,可再现红斑和多形核白细胞(PMN)浸润的疾病特征。GlycoMira已经合成了几种常见多糖的部分亲脂性硫酸盐衍生物,这些衍生物在纳克/毫升浓度下显示出抗炎活性,包括抑制阳离子PMN蛋白酶人白细胞弹性酶(HLE)和抑制PMN粘附受体p -选择素。最重要的是,这些磺化和烷基化的多糖有效地抑制了晚期糖基化终产物受体(RAGE)与其许多配体的相互作用,包括羧基甲基赖氨酸白蛋白(CML-BSA)、S100 calgranulins和高迁移率盒基蛋白-1 (HMGB- 1)。这个一期项目将测试一个假设,即局部应用这些专利药物可以作为一种新的治疗酒渣鼻的方法,通过双重作用来中和和抑制这种疾病患者皮肤中过量阳离子抗菌肽的皮肤炎症活性。在Aim 1中,将合成16个类似物并对其进行化学表征,通过改变分子大小、磺化和烷基化来探索结构-活性空间。在Aim 2中,我们将确定这些化合物作为p -选择素、HLE和RAGE与四种配体相互作用抑制剂的生化活性。在Aim 3中,我们将评估使用这些化合物阻止ll -37诱导的人角质形成细胞分泌IL-8的可行性。利用体外实验中最具活性的两种化合物,在Aim 4中,我们将证明使用这些选定的活性化合物来减少小鼠皮下注射LL-37后局部红斑和真皮PMN浸润的可行性。在这项可行性研究之后,GlycoMira将继续进行II期项目,以利用我们的主要药物的局部应用配方的开发,证明其局部阻断真皮内注射LL-37的皮肤毒性的功效,并完成临床前毒理学研究,以支持提交研究性新药申请。公共卫生相关性:酒渣鼻是一种常见的毁容皮肤病,影响了美国30岁以上人口的3%,即1400万美国人。酒渣鼻主要发生在凯尔特血统的高加索女性身上,其特征是面部红斑,毛细血管增生明显,常伴有丘疹和脓疱。酒糟鼻还会导致眼睛干燥、发痒,男性还会出现球根状鼻部增厚或鼻肿。这种疾病无法治愈,其治疗在很大程度上是经验主义和不完善的。我们建议开发阴离子,部分亲脂性透明质酸衍生物,作为第一个基于机械的治疗这种慢性,毁容性皮肤疾病。

项目成果

期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Novel sulfated polysaccharides disrupt cathelicidins, inhibit RAGE and reduce cutaneous inflammation in a mouse model of rosacea.
  • DOI:
    10.1371/journal.pone.0016658
  • 发表时间:
    2011-02-09
  • 期刊:
  • 影响因子:
    3.7
  • 作者:
    Zhang J;Xu X;Rao NV;Argyle B;McCoard L;Rusho WJ;Kennedy TP;Prestwich GD;Krueger G
  • 通讯作者:
    Krueger G
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THOMAS PRESTON KENNEDY其他文献

THOMAS PRESTON KENNEDY的其他文献

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{{ truncateString('THOMAS PRESTON KENNEDY', 18)}}的其他基金

Novel Glycosaminoglycan Ethers for Prevention of Metastasis
用于预防转移的新型糖胺聚糖醚
  • 批准号:
    8121926
  • 财政年份:
    2011
  • 资助金额:
    $ 14.98万
  • 项目类别:
Novel Glycosaminoglycan Derivatives for Treatment of Bladder Inflammation
用于治疗膀胱炎症的新型糖胺聚糖衍生物
  • 批准号:
    8198976
  • 财政年份:
    2011
  • 资助金额:
    $ 14.98万
  • 项目类别:
Preclinical Development of JS-K, a Novel NO-Generating Prodrug for Cancer
JS-K(一种新型 NO 生成癌症前药)的临床前开发
  • 批准号:
    8424339
  • 财政年份:
    2010
  • 资助金额:
    $ 14.98万
  • 项目类别:

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