Sulfated Polysaccharide Derivatives for the Treatment of Rosacea

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%的人口超过30岁，或14万美国人。在男性和女性的凯尔特起源，酒渣鼻的原因中央红斑的脸，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，酒渣鼻可以破坏鼻子的皮肤，形成经典的“W.C.菲尔兹的鼻子，或者叫鼻赘。酒渣鼻的分子病因学是皮肤过度产生阳离子抗菌肽cathelicidins及其加工丝氨酸蛋白酶。向小鼠皮肤中注射Rosacea样浓度的hCAP 18的37-氨基酸C-末端切割产物（称为LL-37），再现了该疾病特征性的发红和多形核白细胞（PMN）浸润。GlycoMira已经合成了几种常见多糖的部分亲脂性硫酸化衍生物，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蛋白酶（HLE）和抑制PMN粘附受体P-选择素。最重要的是，这些硫酸化和烷基化多糖有效地抑制晚期糖基化终产物受体（CAMP）与其许多配体（包括羧甲基赖氨酸白蛋白（CML-BSA）、S100钙粒蛋白和高迁移率盒族蛋白-1（HMGB- 1））的相互作用。该I期项目将测试以下假设：这些专利药物的局部应用可通过电荷中和和抑制患有这种疾病的患者皮肤中过量阳离子cathelicidins的皮肤炎症活性的双重作用而用作酒渣鼻的新型疗法。在目标1中，将合成16个类似物，并通过改变分子大小、硫酸化和烷基化来进行化学表征以探索结构-活性空间。在目标2中，我们将确定这些化合物作为P-选择素，HLE抑制剂的生物化学活性，以及与四种配体的相互作用。在目标3中，我们将评估使用这些化合物来防止LL-37诱导的培养的人角质形成细胞分泌IL-8的可行性。使用来自体外实验的两种最具活性的化合物，在目的4中，我们将证明使用这些选择的活性化合物减少小鼠中响应于皮下注射LL-37的局部红斑和真皮PMN浸润的可行性。在这项可行性研究之后，GlycoMira将开展一个II期项目，以利用我们的先导药物的局部应用制剂的开发，证明其局部阻断皮肤内注射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性皮肤病，影响3%的美国30岁以上人口，或1400万美国人。酒渣鼻主要困扰凯尔特血统的高加索妇女，其特征是面部红斑，伴有高度可见的毛细血管扩张，通常伴有丘疹和脓疱。酒渣鼻也可以产生干燥，发痒的眼睛，并在男性，一个球状增厚的鼻子，或鼻赘。这种疾病无法治愈，其治疗在很大程度上是经验性的和不完善的。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机械为基础的治疗这种慢性，毁容皮肤疾病。

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.