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

HMG-CoA 还原酶抑制剂作为治疗耐格里变形虫感染的新药

基本信息

批准号：
9979269
负责人：
Anjan Debnath
金额：
$ 23.63万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-02-01 至 2022-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9979269
关键词：
3-hydroxy-3-methylglutaryl-coenzyme A Active Sites Adverse effects Amino Acid Substitution Amoeba genus Amphotericin B Animal Model Antifungal Agents Biochemical Biochemistry Biological Biology Brain Catalytic Domain Cells Centers for Disease Control and Prevention (U.S.)Cessation of life Child Cholesterol Clinical Research Combined Modality Therapy Data Development Dose Drug Industry Drug Kinetics Drug usage Economics Enzymes Ergosterol European FDA approved Fatality rate Foundations Future Genes Genome Human Hydroxymethylglutaryl-CoA Reductase Inhibitors Hydroxymethylglutaryl-CoA reductase In Vitro Inbred BALB C Mice Individual Infection Intervention Membrane Miltefosine Modeling Molecular Target Naegleria Naegleria fowleri National Institute of Allergy and Infectious Disease Outcome Parasites Parasitology Patients Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacodynamics Phenotype Physiological Plasma Production Protein Chemistry Proteins Rare Diseases Recombinants Regimen Research Safety Simvastatin Sterol Biosynthesis Pathway Sterols Testing Therapeutic Agents Time Translating Water Work antimicrobial assay development base biodefense blood-brain barrier permeabilization drug discovery druggable target efficacy study efficacy testing experimental study in vivo in vivo evaluation inhibitor/antagonist interest intraperitoneal isoprenoid lipophilicity mevalonate mortality mouse model novel novel therapeutics off-label use pathogen pharmacokinetics and pharmacodynamics preclinical study primary amebic meningoencephalitis programs small molecule inhibitor

项目摘要

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.

项目概要原发性阿米巴脑膜脑炎 (PAM) 由自由生活的阿米巴原虫福氏耐格里阿米巴 (Naegleria fowleri) 引起，已导致死亡率达97%以上。尽管被认为罕见（但可能报告不足），但它是一种死亡率很高的感染。那里不是 FDA 批准的治疗 PAM 的药物。 CDC建议使用抗真菌药物两性霉素 B 和抗利什曼病药物米替福辛，但接受联合治疗的患者很少存活。因此，开发有效的药物是避免未来死亡的一个未满足的关键需求。因为这是一个罕见的疾病，制药行业和为此进行的药物发现工作很少感染很大程度上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对福氏奈瑟菌具有杀阿米巴作用；细胞生物学研究提供的证据表明这些抑制剂针对的是寄生虫 HMGR。针对单个分子的新型 HMGR 抑制剂的鉴定目标以及基于目标的方法与表型活动的结合为本提案奠定了基础。根据我们的初步数据，我们建议 1) 测试他汀类药物对寄生虫重组 HMGR 的作用，2) 对两种有前景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，3) 在 PAM 动物模型中测试这两种他汀类药物的体内功效。这血脑屏障渗透性 HMGR 抑制剂的鉴定以及生化和联合治疗寄生虫学专业知识将产生适合治疗 PAM 的新型抗菌药物。