Fungal Metabolites as Novel Anthelmintics against Soil-Transmitted Helminthes.

描述(申请人提供)：标题：真菌代谢物作为防治土传蠕虫的新型驱虫剂项目摘要/摘要据估计，全球有超过20亿人因感染土传蠕虫(STH)而患有并发症，但人类健康制药公司进行的研究很少。在美国，据估计，在贫困地区，略低于400万人患有未确诊的性传播感染。STH感染通常影响那些生活在贫困中和代表性不足的少数群体。移民、国际旅行的增加以及从性病流行国家返回的美国士兵带来了未确诊的蠕虫感染。目前迫切需要新的抗寄生虫药物来治疗由钩虫、蛔虫、鞭虫和类圆线虫等性传播疾病引起的人类胃肠道疾病。目前的治疗方法是驱虫药，这种药物来自兽药，而不是专门为人类开发的产品。虽然这些产品在许多情况下是有效的，但耐药性的出现，加上低效和大规模不分青红皂白的药物治疗，导致需要发现和开发新的治疗方法。MyCosynthetix真菌文库代表了一种具有潜在驱虫活性的新代谢物的来源，基于它们对其他医学重要目标的活性在第一阶段，我们将评估从1500种真菌和100种纯真菌代谢物中提取的提取物的能力，以了解它们抑制人类寄生虫STRongyloids stercoris感染阶段的运动和动物寄生虫Haemonchus Torortus的运动和发育的能力，该种寄生虫将作为人类GI寄生虫的替代品。对这两种生物的初步筛选实验表明，我们能够在Mycoynthetix真菌提取物中检测到对这两种蠕虫中的一种或两种都具有显著的活性。在第一阶段，预计我们将根据我们过去在传染病项目中的经验，利用整个生物体来评估原始微生物材料，并根据初步数据确定15-45种活性真菌提取物/化合物。使用适当的生物学方法，我们将根据与哺乳动物细胞系的比较研究中测量的活性和高治疗指数，将这些先导分为10-15个先导。活性真菌将被更大规模地培养，以获得足够的物质，用于利用柱层析法浓缩活性成分。在第一阶段结束时，我们预计将能够确定5-10个浓缩提取物先导，对一种或两种寄生虫具有良好的活性和治疗指数。第二阶段将是扩大筛选活动，并利用化学和药理学对线索进行进一步评估，以满足有兴趣治疗这些疾病的潜在制药公司(人类和/或动物)的要求。一种新驱虫剂的发现和开发将满足人类和动物卫生部门的巨大和关键市场需求。对人和动物蠕虫病新出现的驱虫药耐药性导致识别和使用植物药物和其他天然产品来抗击这些感染。Mycoynthetix将利用制药合作伙伴识别、开发和销售用于治疗STH的新型驱虫药。

DESCRIPTION (provided by applicant): Title: Fungal Metabolites as Novel Anthelmintics against Soil-Transmitted Helminthes Project Summary/Abstract It is estimated that over 2 billion people worldwide are suffering from complications due to infections with soil transmitted helminthes (STHs), but very little research is being conducted by human health pharmaceutical companies. In the USA, it is estimated that in distressed areas of poverty, just under 4 million people harbor undiagnosed STH infections. STH infections typically affect those living in poverty and underrepresented minority populations. Increased immigration, international travel and US soldiers returning from STH endemic countries are bringing undiagnosed helminth infections with them. There is an urgent need for new anti-parasitic agents for treating human gastrointestinal diseases caused by the STHs such as hookworm, ascarid, whipworm and strongyloides. Current treatment is by anthelmintics, which were derived from veterinary medicine rather than products developed specifically for humans. While in many instances these products are effective, the emergence of resistance coupled with low efficacy and mass indiscriminate drug treatment has resulted in the need for new therapeutics to be discovered and developed. The Mycosynthetix fungal library represents a source of novel metabolites with potential anthelmintic activity based on their activity against other targets of medical importance In Phase I we will evaluate extracts taken from 1500 fungi and 100 pure fungal metabolites for their ability to inhibit the motility of the infective stages of the human parasite Strongyloides stercoralis and the motility and development of the animal parasite Haemonchus contortus which will act as a surrogate for human GI parasites. Preliminary experiments against validated screens of these two organisms, demonstrated we were able to detect significant activity against one or both of these worms in Mycosynthetix fungal extracts. During Phase 1, it is anticipated that we will identify between 15-45 active fungal extracts/ compounds based on our past experience with infectious disease programs using whole organisms to evaluate crude microbial material, and on the preliminary data. Using appropriate biological methods we will prioritize these into 10-15 leads by activity and high therapeutic index as measured in comparison studies with mammalian cell lines. Active fungi will be cultured on a larger scale to obtain enough material for enrichment of the active component using column chromatography. At the end of Phase I, we will expect to be able to identify 5-10 Enriched Extract Leads having good activity and therapeutic index against one or both parasites. Phase II will be an expanded screening campaign and further evaluation of leads using both chemistry and pharmacology to satisfy the requirements of prospective pharmaceutical companies (human and/or animal) with interest in treating these diseases. Discovery and development of a new anthelmintic will satisfy a large and critical market need in both the human and animal health sectors. Emerging anthelmintic resistance against human and animal helminthiasis has led to resurgence in the identification and use of phytomedicines and other natural products to combat these infections. Mycosynthetix will identify, develop and market novel anthelmintics for treatment against STHs using pharmaceutical partners.