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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：
10088397
负责人：
Anjan Debnath
金额：
$ 19.72万
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 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10088397
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.

项目总结由自由生活的鸡内阿米巴引起的原发性阿米巴性脑膜脑炎(PAM)具有致命性。治愈率超过97%。虽然被认为是罕见的(但可能被低估了)，但它是一种死亡率很高的感染。那里没有FDA批准的治疗PAM的药物。疾控中心建议使用抗真菌药物两性霉素 B和一种抗利什曼药物米替福辛，但接受联合治疗的患者很少能存活下来。因此，开发有效的药物是避免未来死亡的一个关键的未得到满足的需求。因为这是一种罕见的疾病，制药业的药物发现工作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作为阿米德杀菌剂；细胞生物学研究提供了证据这些抑制剂针对寄生虫HMGR。靶向单个分子的新型HMGR抑制剂的鉴定目标和以目标为基础的方法与表型活动的结合为这一提议奠定了基础。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)测试他汀类药物对寄生虫重组HMGR的作用两种有希望的血脑屏障的耐受性及药代动力学-药效学研究 3)在PAM动物模型中测试这两种他汀类药物的体内疗效。这个血脑屏障通透性HMGR抑制剂的鉴定及生化联合应用寄生虫学的专业知识将生产出适合治疗PAM的新的抗菌剂。

项目成果

期刊论文数量（11）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Domain-Swap Dimerization of Acanthamoeba castellanii CYP51 and a Unique Mechanism of Inactivation by Isavuconazole.

卡氏棘阿米巴 CYP51 的结构域交换二聚化和艾沙康唑独特的灭活机制。

DOI：
10.1124/molpharm.120.000092
发表时间：
2020
期刊：
Molecular pharmacology
影响因子：
3.6
作者：
Sharma,Vandna;Shing,Brian;Hernandez-Alvarez,Lilian;Debnath,Anjan;Podust,LarissaM
通讯作者：
Podust,LarissaM

A Broad Spectrum Antiparasitic Activity of Organotin (IV) Derivatives and Its Untargeted Proteomic Profiling Using Leishmania donovani.