HMG-CoA Reductase Inhibitors as New Drug Leads for Naegleria Infection

项目摘要 原发性阿米巴脑膜脑炎（PAM）是由一种自由生活的福氏内阿米巴（Naegleria fowleri）引起的， 率超过97%。虽然被认为是罕见的（但可能被低估），但它是一种死亡率很高的感染。那里 还没有FDA批准的治疗PAM的药物疾病控制中心建议使用抗真菌药物白藜芦醇 B和一种抗利什曼病药物米替福新，但很少有患者接受联合治疗后存活。 因此，开发有效药物是避免未来死亡的一个关键的未满足需求。因为这是一种罕见的 疾病，制药业和药物发现对此缺乏药物发现努力 感染主要依赖于学术研究中心。我们的初步研究确定了HMG-CoA还原酶 （HMGR）抑制剂或他汀类药物作为针对N.细胞生物学研究提供了证据， 这些抑制剂靶向寄生虫HMGR。靶向单个分子的新型HMGR抑制剂的鉴定 目标和基于目标的方法与表型活性的结合为这一提议奠定了基础。 基于我们的初步数据，我们建议1）测试他汀类药物对寄生虫重组HMGR的作用，2） 对两种有前途的血脑屏障进行耐受性和药代动力学-药效学研究 渗透性他汀类药物和3）测试这两种他汀类药物在PAM动物模型中的体内功效。的 血脑屏障可渗透HMGR抑制剂的鉴定以及生物化学和 寄生虫学专业知识将产生新的抗菌剂，适用于治疗PAM。

PROJECT SUMMARY Primary Amebic Meningoencephalitis (PAM), caused by a free-living ameba Naegleria fowleri, has a fatality rate of over 97%. Though considered rare (but likely underreported), it is an infection with high mortality. There are no FDA-approved drugs to treat PAM. The CDC recommends the use of the antifungal drug amphotericin B and an antileishmanial drug miltefosine but few patients treated with the combination therapy have survived. Therefore, development of efficient drugs is a critical unmet need to avert future deaths. Because this is a rare disease, there is a paucity of drug discovery efforts by the pharmaceutical industry and drug discovery for this infection largely relies on academic research centers. Our preliminary studies identified HMG-CoA reductase (HMGR) inhibitors or statins as amebicidal against N. fowleri; cell biological studies provided evidence that these inhibitors targeted parasite HMGR. Identification of novel HMGR inhibitors targeting individual molecular target and combination of target-based approach with phenotypic activity laid the foundation for this proposal. Based on our preliminary data, we propose 1) to test statins against parasite recombinant HMGR, 2) to conduct tolerability and pharmacokinetic-pharmacodynamic studies of two promising blood-brain barrier permeable statins and 3) to test in vivo efficacy of these two statins in an animal model of PAM. The identification of blood-brain barrier permeable HMGR inhibitors and combination of biochemical and parasitological expertise will produce new antimicrobials that are suitable for the treatment of PAM.