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Development of Novel MetAP2 inhibitors as potential therapeutics for Microsporidiosis

开发新型 MetAP2 抑制剂作为微孢子虫病的潜在疗法

基本信息

批准号：
10214531
负责人：
Bhaskar Chandra Das
金额：
$ 40.13万
依托单位：
LONG ISLAND UNIVERSITY BROOKLYN CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-01 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10214531
关键词：
Acquired Immunodeficiency Syndrome Antiparasitic Agents Binding Bioinformatics Biological Assay Biological Availability Bone Marrow Categories Category B pathogen Cells Characteristics Clinical Crystallization Data Development Diarrhea Disease Dose Drug Design Drug Targeting Encephalitozoon cuniculi Endothelial Cells Enterocytozoon bieneusi Enzyme Inhibition Enzymes Eukaryota Food Gastrointestinal tract structure Genes Goals Grant Growth Human Immune Immunocompetent In Vitro Industry Infection Invertebrates Lead Leishmania donovani Libraries Mammals Mass Spectrum Analysis Microsporidia Microsporidiosis Modeling Morbidity - disease rate Nosema corneum Opportunistic Infections Organism Parasitology Pathogenicity Patients Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Plasmodium falciparum Process Property Protozoa Publications Recombinants Research Resistance Respiratory Muscles Saccharomyces cerevisiae Structure Structure-Activity Relationship Testing Therapeutic Therapeutic Agents Thrombocytopenia Toxic effect United States National Institutes of Health Vertebrates Water Yeasts Zoonoses analog base burden of illness design drug development drug structure emerging pathogen fumagillin high throughput screening improved in silico in vitro testing in vivo in vivo Model inhibitor/antagonist interest methionyl aminopeptidase mortality mouse model nervous system infection novel novel drug class novel therapeutics opportunistic pathogen pathogen pharmacokinetics and pharmacodynamics preclinical development reproductive scaffold screening structural biology therapeutic target therapy design tool

项目摘要

Abstract This application represents an approach to rational drug design for the treatment of microsporidiosis using structure activity relationships (SAR) for agents that inhibit Methionine Aminopeptidase type 2 (MetAP2). Microsporidiosis is an emerging zoonotic infection that is an opportunistic pathogen in the setting of AIDS, but is also seen in other immune compromised hosts as well as immune competent hosts. Current therapies are suboptimal. The hypothesis underlying this type of grant is that differences in the structure of the drug target between host and pathogen will permit the design of selective therapeutic agents with decreased host toxicity. The initial choice in drug design is the selection of the target among the dozens of potential targets. MetAP2 is an extremely logical therapeutic target for these pathogens. Microsporidia lack Methionine Aminopeptidase type 1 (MetAP1) making MetAP2 an essential enzyme. Among eukaryotes this makes them highly susceptible to MetAP2 inhibitors and limits the toxicity of these compounds in their hosts as humans have both MetAP1 and MetAP2. Use of Fumagillin and its derivatives, which are non-competitive inhibitors that covalently bind to and inhibit MetAP2 (but not MetAP1), has confirmed that inhibition of MetAP2 is an effective in vitro and in vivo therapeutic target for many species of microsporidia. In fact, Fumagillin has been demonstrated to have efficacy in humans infected with Enterocytozoon bieneusi; however, its use has been limited by bone marrow toxicity. Our research group has cloned, expressed and determined the crystal structure of the MetAP2 of the microsporidian Encephalitozoon cuniculi (i.e. EcMetAP2) as well as developed yeast dependent on EcMetAP2 for growth. We have identified and cloned Ent.bieneusi MetAP2 (EbMetAP2). Exploiting differences in the structure of MetAP2 between host and pathogen should permit the design of selective therapeutic competitive inhibitors of MetAP2 with decreased host toxicity. These new inhibitors will be tested in vitro and in vivo for efficacy and in an iterative process we will use this information to refine our models and improve inhibitor design. Using this Limited Rational Design (LRD) approach we will generate new libraries based on our lead compounds that will then be modified to generate new libraries to improve their selectivity and pharmacologic properties. We have already identified two lead compounds, BL6 and D63, from our initial LRD/SAR studies that have increased selectivity for microsporidian MetAP2 and efficacy in our in vitro and in vivo models of microsporidiosis. Since MetAP2 is important in other protozoa our lead compounds should also define new classes of drugs that could have broad anti-parasitic activity and prove useful in the treatment of other infections. Our assembled research group containing experts in medicinal chemistry, parasitology, bioinformatics, mass spectrometry and structural biology as well as industry consultants has the necessary complementary expertise to develop and test these compounds.

抽象的该申请代表了一种用于治疗微孢子虫病的合理药物设计方法抑制 2 型蛋氨酸氨肽酶 (MetAP2) 的药物的结构活性关系 (SAR)。微孢子虫病是一种新出现的人畜共患感染，是艾滋病环境中的机会致病菌，但也见于其他免疫受损的宿主以及免疫能力强的宿主。目前的治疗方法有次优。此类资助的假设是药物靶标结构的差异宿主和病原体之间的研究将允许设计具有降低宿主毒性的选择性治疗剂。药物设计的最初选择是在数十个潜在靶点中选择靶点。 MetAP2 是这些病原体的一个非常合乎逻辑的治疗目标。微孢子虫缺乏甲硫氨酸氨基肽酶 1 型 (MetAP1) 使 MetAP2 成为必需酶。在真核生物中，这使得它们高度敏感 MetAP2 抑制剂并限制这些化合物在宿主体内的毒性，因为人类同时具有 MetAP1 和 MetAP2。使用夫马洁林及其衍生物，它们是共价结合的非竞争性抑制剂并抑制MetAP2（但不是MetAP1），已证实抑制MetAP2在体外和体内均有效许多种微孢子虫的治疗靶点。事实上，夫马洁林已被证明具有对感染比氏肠细胞虫的人类的功效；然而，它的使用受到骨髓的限制毒性。我们课题组克隆、表达并测定了MetAP2的晶体结构微孢子虫 EcMetAP2 以及依赖 EcMetAP2 的发达酵母为了成长。我们已经鉴定并克隆了 Ent.bieneusi MetAP2 (EbMetAP2)。利用差异宿主和病原体之间的 MetAP2 结构应允许设计选择性治疗竞争性药物 MetAP2 抑制剂，可降低宿主毒性。这些新抑制剂将在体外和体内进行测试功效，在迭代过程中，我们将使用这些信息来完善我们的模型并改进抑制剂设计。使用这种有限理性设计（LRD）方法，我们将根据我们的领先优势生成新的库然后对化合物进行修饰以生成新的文库，以提高其选择性和药理学特性。我们已经从最初的 LRD/SAR 研究中鉴定出两种先导化合物：BL6 和 D63 增加了对微孢子虫 MetAP2 的选择性以及在我们的体外和体内模型中的功效微孢子虫病。由于 MetAP2 在其他原生动物中很重要，我们的先导化合物也应该定义新的具有广泛抗寄生虫活性并被证明可用于治疗其他疾病的药物类别感染。我们组建的研究小组由药物化学、寄生虫学、生物信息学、质谱和结构生物学以及行业顾问拥有必要的开发和测试这些化合物的补充专业知识。