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：
10381678
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 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10381678
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 interest methionyl aminopeptidase mortality mouse model nervous system infection novel novel drug class novel therapeutics opportunistic pathogen pathogen pharmacokinetics and pharmacodynamics preclinical development rational design 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.

抽象的该应用代表了使用合理药物设计的方法，用于使用抑制蛋氨酸氨基肽酶2型（METAP2）的药物的结构活性关系（SAR）。微孢子虫病是一种新兴的人畜共患感染，在艾滋病的环境中是机会性病原体，但还可以在其他免疫损害的宿主以及免疫胜任的宿主中看到。当前的疗法是次优。这种类型的赠款基础的假设是药物靶标的结构差异在宿主和病原体之间，可以设计选择性治疗剂，宿主毒性降低。药物设计的最初选择是数十个潜在靶标的目标选择。 Metap2是这些病原体的极其逻辑的治疗靶标。微孢子虫缺乏蛋氨酸氨基肽酶 1型（METAP1）使Metap2成为必不可少的酶。在真核生物中，这使它们非常容易受到影响 Metap2抑制剂并限制了这些化合物在其宿主中的毒性，因为人类都有Metap1 和metap2。使用Fumagillin及其衍生物，它们是非竞争性抑制剂，共价结合并抑制METAP2（但不是Metap1），已经确认抑制Metap2是一种有效的体外和体内许多微孢子虫种类的治疗靶标。实际上，已证明富马吉林有感染肠肠细胞生物素的人类的功效；但是，它的使用受到骨髓的限制毒性。我们的研究小组已经克隆，表达和确定了Metap2的晶体结构微孢子虫脑脑cuniculi（即ecmetap2）以及依赖于Ecmetap2的酵母菌开发为了增长。我们已经确定并克隆了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力 Metap2的抑制剂，宿主毒性降低。这些新抑制剂将在体外和体内进行测试功效和迭代过程中，我们将使用此信息来完善我们的模型并改善抑制剂设计。使用这种有限的理性设计（LRD）方法，我们将根据我们的潜在客户生成新的库然后将修改以生成新图书馆以提高其选择性和药理学的化合物特性。我们已经从我们的初始LRD/SAR研究中鉴定出了两种铅化合物BL6和D63 在我们的体外和体内模型中，对微孢子虫Metap2和疗效的选择性提高了微孢子虫病。由于Metap2在其他原生动物中很重要，我们的铅化合物也应定义新的可能具有广泛抗寄生活性并证明对其他治疗的药物类别感染。我们组装的研究小组，其中包含药物化学专家，寄生虫学，生物信息学，质谱和结构生物学以及行业顾问有必要开发和测试这些化合物的补充专业知识。