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

描述（由申请人提供）：E。溶组织原虫是一种原生动物肠道寄生虫，能够侵入和破坏人体组织，导致潜在的危及生命的疾病，如肠道结肠炎和肝脓肿。阿米巴感染影响世界人口的大约10%，在大约5000万人中引起侵袭性疾病，并且每年导致100，000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重要的病理机制，其可导致宿主细胞死亡和系统性侵袭。严重的肠道阿米巴感染需要用混合阿米巴杀剂甲硝唑治疗，甲硝唑对肠道和全身阿米巴病都有效。甲硝唑的一个局限性是其在上消化道中的高吸收，这可能导致无法以治疗浓度到达结肠和全身副作用。本提案的目的是开发一种新型的双功能聚合物阿米巴治疗剂，半乳糖-右旋糖酐-甲硝唑（Gal-Dextran-MM）前药，用于甲硝唑和半乳糖的结肠特异性递送。这种杀阿米巴治疗剂旨在通过两种机制阻断疾病进展并根除潜在感染，1）递送杀阿米巴剂甲硝唑以杀死阿米巴原虫，和2）递送半乳糖，其可抑制寄生虫与宿主细胞的粘附。中心假设是半乳糖-葡聚糖-MM将稳定地通过上胃肠道，在结肠中存在的微生物内切葡聚糖酶进行葡聚糖解聚后释放药物和半乳糖，并抑制阿米巴病的进展。具体目的是：1）合成和表征Gal-葡聚糖-MM作为结肠特异性双功能聚合物杀阿米巴前药，2）评价Gal -葡聚糖-MM的体外杀阿米巴活性和粘附抑制作用，3）评价Gal-葡聚糖-MM在小鼠阿米巴溃疡模型中的体内疗效和毒性。公共卫生相关性：寄生阿米巴感染导致轻度至重度肠道疾病，如果生物体定植在敏感器官如大脑和肝脏，则可能危及生命。世界人口的10%受到这种感染的影响。由于传播和感染的容易性，aomeba也被认为是潜在的生物恐怖主义制剂。因此，持续需要开发针对E.以对抗大规模爆发。本项目的重点是开发一种新的结肠特异性双功能阿米巴治疗药物，半乳糖-右旋糖酐-甲硝唑（Gal-Dextran-MM）前药，用于治疗阿米巴病。

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.