A Novel Colon-specific Bi-functional Amebicidal Therapeutics: Gal-Dextran-MM

新型结肠特异性双功能杀阿米巴疗法：Gal-Dextran-MM

基本信息

批准号：
7896642
负责人：
Jeoung Soo Lee
金额：
$ 7.35万
依托单位：
CLEMSON UNIVERSITY
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：
2009-07-22 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7896642
关键词：
Adherence Adhesions Adverse effects Affect Africa Amebiasis Amebic colitis Amebicides Amoeba genus Area Asia Bioterrorism Brain Categories Cell Adhesion Cell Communication Cell Death Cells Cessation of life Characteristics Colitis Colon Cyst Development Dextranase Dextrans Disease Disease Outbreaks Disease Progression Dose Entamoeba Entamoeba histolytica Enteral Enzymes Epithelial Cells Failure Food Galactosamine Galactose Genus Cola High Pressure Liquid Chromatography In Vitro Infection Intestines Invaded Large Intestine Lead Lectin Life Liver Liver Abscess Membrane Proteins Methods Metronidazole Modeling Mucous body substance Mus National Institute of Allergy and Infectious Disease Nitroimidazoles Organ Organism Parasites Parasitic infection Pathology Pharmaceutical Preparations Population Prevalence Prodrugs Protozoa Rattus Reporting Side Site Small Intestines South America Spectroscopy, Fourier Transform Infrared Stomach Structure Testing Therapeutic Toxic effect Ulcer United States Upper digestive tract structure Vertebral column Water World Health Organization absorption base chemical stability cytotoxicity depolymerization design dextran effective therapy esterase human tissue in vivo in vivo Model innovation killings microbial novel pathogen public health relevance transmission process

项目摘要

DESCRIPTION (provided by applicant): E. histolytica is a protozoal enteric parasite that is capable of invading and destroying human tissues, leading to potentially life-threatening diseases such as enteric colitis and liver abscess. Amoebic infection affects approximately 10% of the world's population, causing invasive disease in about 50 million people and resulting in 100,000 deaths annually. Parasite adhesion to host intestinal epithelial cells, through a glactose/N-acetyl galactosamine lectin, is a critical mechanism of pathology, which can lead to host cell death and systemic invasion. Severe intestinal amoebic infection requires treatment with the mixed amebicide, metronidazole, which is effective against both intestinal and systemic amebiasis. One limitation of metronidzole is its high absorption in the upper GI tract , that may result in failure to reach the colon in therapeutic concentrations and in systemic side effects. The objective of this proposal is to develop a novel bi-functional polymeric amebicidal therapeutic, Galactose-Dextran- Metronidazole (Gal-Dextran-MM) prodrug, for colon-specific delivery of metronidazole and galactose. This amebicidal therapeutic is designed to block disease progression and eradicate the underlying infection through two mechanisms, 1) delivery of the amebicidal agent, metronidazole, to kill the amoebae, and 2) delivery of galactose which may inhibit adhesion of the parasite to host cells. The central hypothesis is that Gal-dextran-MM will stably pass through the upper GI tract, release drug and galactose following dextran depolymerization by microbial endodextranases present in the colon, and inhibit the progression of amebiasis. The specific aims are 1) to synthesize and characterize Gal- Dextran-MM as a colon-specific bi-functional polymeric amebicidal prodrug, 2) to evaluate the amebicidal activity and adhesion inhibition effect of Gal -Dextran -MM in vitro, and 3) to evaluate the efficacy and toxicity of Gal-Dextran-MM in a mouse amoebic ulcer model in vivo. PUBLIC HEALTH RELEVANCE: Infection by parasitic amoeba results in mild to severe bowel disorders and potentially life threatening diseases if the organism colonizes sensitive organs such as the brain and the liver. As many of 10% of the world population are affected by this infection. Due to the ease of transmission and infection, aomeba are also considered potential bioterrorism agents. Therefore, there is a continued need for the development of innovative therapeutic strategies for E. histolytica in order to counter large scale outbreaks. This project is focused on development of a novel colon-specific bi-functional amebicidal therapeutic, Galactose-Dextran-Metronidazole (Gal-Dextran-MM) prodrug, for treatment of amebiasis.

描述（由申请人提供）：溶组织内阿米巴是一种原虫肠道寄生虫，能够侵入并破坏人体组织，导致潜在危及生命的疾病，例如肠结肠炎和肝脓肿。阿米巴感染影响着世界约 10% 的人口，导致约 5000 万人罹患侵袭性疾病，每年导致 10 万人死亡。寄生虫通过半乳糖/N-乙酰半乳糖胺凝集素粘附到宿主肠上皮细胞上，是一种关键的病理机制，可导致宿主细胞死亡和全身侵袭。严重的肠道阿米巴感染需要使用混合阿米巴杀剂甲硝唑治疗，该药物对肠道和全身阿米巴病均有效。甲硝唑的局限性之一是其在上胃肠道的高吸收，这可能导致治疗浓度无法到达结肠并产生全身副作用。该提案的目的是开发一种新型双功能聚合阿米巴杀治疗药物半乳糖-葡聚糖-甲硝唑（Gal-Dextran-MM）前药，用于结肠特异性递送甲硝唑和半乳糖。这种杀阿米巴治疗剂旨在通过两种机制阻止疾病进展并根除潜在感染：1）输送阿米巴杀剂甲硝唑来杀死阿米巴原虫，2）输送半乳糖，可抑制寄生虫与宿主细胞的粘附。中心假设是Gal-dextran-MM将稳定地通过上胃肠道，在结肠中的微生物内葡聚糖酶解聚葡聚糖后释放药物和半乳糖，并抑制阿米巴病的进展。具体目标是 1) 合成和表征 Gal-Dextran-MM 作为结肠特异性双功能聚合阿米巴杀虫前药，2) 评价 Gal-Dextran-MM 的体外杀阿米巴活性和粘附抑制作用，以及 3)评估 Gal-Dextran-MM 在小鼠阿米巴溃疡模型中的体内功效和毒性。公共卫生相关性：寄生阿米巴原虫感染会导致轻度至重度肠道疾病，如果该生物体定植于大脑和肝脏等敏感器官，则可能会导致危及生命的疾病。世界人口中有 10% 受到这种感染的影响。由于易于传播和感染，变形虫也被认为是潜在的生物恐怖分子。因此，仍然需要开发溶组织内阿米巴的创新治疗策略，以应对大规模爆发。该项目的重点是开发一种新型结肠特异性双功能阿米巴杀治疗剂半乳糖-葡聚糖-甲硝唑（Gal-Dextran-MM）前药，用于治疗阿米巴病。