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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：
10408440
负责人：
Bhaskar Chandra Das
金额：
$ 39万
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 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10408440
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.

摘要