Development of Small Molecule Mimetics of hepatocyte Growth Factor (HGF)

肝细胞生长因子（HGF）小分子模拟物的开发

• 批准号: 8166335
• 负责人: Bhaskar Chandra Das
• 金额: $ 2.65万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-12 至 2011-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8166335
• 关键词: Alcohol abuse; Animal Model; Antibodies; Apoptotic; Biological; Biological Assay; Boron; Canis familiaris; Cell Culture Techniques; Cell Surface Receptors; Cells; Chemistry; Chronic; Cicatrix; Cirrhosis; Collagen; Cyst; Development; Dose; Epithelial Cells; Evaluation; Fibrosis; Growth Factor Interaction; Hepatitis; Hepatitis C; Hepatocyte; Hepatocyte Growth Factor; Infection; Injury; Kidney; Liver; Liver Cirrhosis; Liver Fibrosis; Liver diseases; Modeling; Normal Cell; Organogenesis; Pathway interactions; Peptides; Production; Proteins; Publishing; Pulmonary Fibrosis; Rattus; Recovery; Regulation; Signal Transduction; Specificity; Staging; Structure; Technology; Testing; Therapeutic; Therapeutic Uses; Tissues; Tube; Vascular Endothelial Cell; Work; Wound Healing; angiogenesis; base; cell type; cytokine; design; injured; interest; kidney cell; liver transplantation; meetings; melanocyte; mimetics; monolayer; morphogens; organ regeneration; polypeptide; relating to nervous system; response; small molecule

DESCRIPTION (provided by applicant): The naturally-occurring cytokine hepatocyte growth factor (HGF), also known as scatter factor(SF), is active in numerous tissues throughout the body, participating in the regulation of angiogenesis, organogenesis, tissue repair and neural induction. HGF is 1) mitogenic in many normal cell types, including hepatocytes, vascular endothelial cells, and melanocytes; 2) a morphogen that promotes the formation of branched tube-like structures in epithelial cells; 3) cytoprotective by virtue of its anti-apoptotic activity and exerts anti-fibrotic effects by opposing TGFbeta1-Smad signaling. All biological effects of HGF are triggered by stimulating its cell surface receptor c-Met, with concomitant activation of downstream effector pathways. Several recently published studies have documented the therapeutic potential of exogenously administered SF/HGF in animal models of renal, pulmonary and liver fibrosis. Administration of HGF into injured liver tissue suggests that the cytokine is effective in promoting tissue repair and organ regeneration and in reducing fibrosis. HGF effectively alleviates the structural damage seen in liver cirrhosis, an end-stage liver disease that is frequently caused by Hepatitis C infection or long-term alcohol abuse. Given it's therapeutic potential, there is heightened interest in the development of HGF mimetics that can activate c-Met. To date, an HGF-derived peptide and c-Met activating antibodies have been developed, yet those polypeptide-based mimetics are unstable and expensive. To overcome these shortcomings, we will develop small molecule mimetics of HGF activity. In Aim 1, we will design such small molecules using our LRD (Limited rational design) approach and synthesize them using synthetic organic technology. In aim 2, we will test the activity of our newly developed compounds in epithelial cell culture models. PUBLIC HEALTH RELEVANCE: Administration of Hepatocyte Growth Factor (HGF), a naturally occurring cytokine, has proven beneficial for the recovery from liver injury during hepatitis infection and during liver transplantation in animal models. It is also the only efficient treatment for chronic liver disease (cirrhosis) that causes a scarring of the liver and steady decline of its function. Cirrhosis is most often caused by Hepatitis C infection and long-term alcohol abuse. However, HGF production is expensive and the manufactured protein is not stable, making it unsuitable for therapeutic use. To circumvent these problems, we will develop small molecule mimetics of HGF that work with equal or better efficacy and specificity and are cheaper to produce and easier to administer than recombinantly made HGF.

描述（由申请人提供）：自然存在的细胞因子肝细胞生长因子（HGF），也称为散射因子（SF），在整个体内的许多组织中都活跃，参与血管生成，器官发生，器官发生，组织修复和神经诱导的调节。 HGF为1）在许多正常细胞类型中的有丝分裂，包括肝细胞，血管内皮细胞和黑素细胞； 2）促进上皮细胞中分支管状结构形成的形态学； 3）细胞保护因素具有抗凋亡活性，并通过反对TGFBETA1-SMAD信号传导发挥抗纤维化作用。 HGF的所有生物学作用都是通过刺激其细胞表面受体C-Met触发的，并随着下游效应途径的激活。最近发表的一些研究记录了在肾脏，肺和肝纤维化动物模型中外源给予SF/HGF的治疗潜力。将HGF施用到受伤的肝组织中表明，细胞因子可有效促进组织修复和器官再生并减少纤维化。 HGF有效地减轻了肝脏肝硬化中看到的结构损害，肝硬化是一种末期肝病，通常是由丙型肝炎感染或长期酗酒引起的。鉴于它具有治疗潜力，因此对可以激活C-MET的HGF模拟物的发展产生了更高的兴趣。迄今为止，已经开发了由HGF衍生的肽和C-MET激活抗体，但是那些基于多肽的模仿型不稳定且昂贵。为了克服这些缺点，我们将发展出小分子的HGF活性。在AIM 1中，我们将使用我们的LRD（有限理性设计）方法来设计如此小的分子，并使用合成有机技术合成它们。在AIM 2中，我们将测试新开发的化合物在上皮细胞培养模型中的活性。 公共卫生相关性：肝细胞生长因子（HGF）是一种天然存在的细胞因子，事实证明，在动物模型中，在肝炎感染期间和肝移植期间从肝损伤中恢复有益。它也是慢性肝病（肝硬化）的唯一有效治疗方法，会导致肝脏的疤痕和其功能稳定下降。肝硬化通常是由丙型肝炎感染和长期酗酒引起的。但是，HGF的生产很昂贵，并且制成的蛋白质不稳定，因此不适合治疗。为了解决这些问题，我们将开发出小的HGF分子模拟物，这些分子具有相等或更好的功效和特异性，并且比重组制作的HGF更便宜，并且更容易施用。