Targeting MraY: Synthesis and Validation of MraY Inhibitors

靶向 MraY：MraY 抑制剂的合成和验证

基本信息

批准号：
7986383
负责人：
Michio Kurosu
金额：
$ 36.75万
依托单位：
COLORADO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-05-15 至 2011-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7986383
关键词：
AIDS/HIV problem Acids Acquired Immunodeficiency Syndrome Amikacin Amino Acids Amino Alcohols Anabolism Anti-Bacterial Agents Anti-HIV Agents Antibiotics Antimycobacterial Agents Antitubercular Agents Applications Grants Behavior Biological Biological Assay Biological Factors Capromycin Cell Line Cells Cessation of life Ciprofloxacin Clinical Combined Modality Therapy Complex Cycloserine Cytochrome P450 3A4 Depsipeptides Development Dose Drug Delivery Systems Drug Kinetics Drug resistance Drug-sensitive Enzymes Ethambutol Ethionamide Evaluation Exhibits Fluorescent Probes Future Generations Genus Mycobacterium Glycopeptides Goals Gram-Positive Bacteria Grant HIV HIV Infections Highly Active Antiretroviral Therapy Hospitals In Vitro Industry Infection Kanamycin Knowledge Laboratory Research Lactams Lead Libraries Life Liver Microsomes Metabolic Modeling Monkeys Multi-Drug Resistance Multidrug-Resistant Tuberculosis Mus Mycobacterium tuberculosis Nucleosides Nucleotides Ofloxacin Patients Penicillin-Binding Proteins Peptidoglycan Pharmaceutical Chemistry Pharmaceutical Preparations Plasma Polymers Population Positioning Attribute Prevention Protease Inhibitor Pyrazinamide RNA-Directed DNA Polymerase Relative (related person)Reporting Research Resistance Reverse Transcriptase Inhibitors Rifampin Route Safety Scientist Screening procedure Series Solutions Source Staphylococcus aureus Streptomyces Structure Time Toxic effect Tuberculosis Tunicamycin UDP-N-acetylmuramic acid pentapeptide Uridine Validation amphomycin analog antimicrobial base chemical property combat cytotoxicity design drug metabolism efficacy evaluation functional group fungus improved in vivo inhibitor/antagonist interest isoniazid kidney cell lipid I methicillin resistant Staphylococcus aureus mouse model novel p-Aminosalicylic Acid programs public health relevance resistant strain response stereochemistry sugar topical antibacterial treatment strategy tuberculosis drugs

项目摘要

DESCRIPTION (provided by applicant): A MraY inhibitor from a natural source, capuramycin, exhibited significant activity in vivo using M. tuberculosis mouse infection model. Muraymycins possess a common core structure of capuramycin, however, their structural diversity is observed in an acyclic complex depsipeptide moiety and the C5'-sugar-appended. Promising in vivo antibactericidal activity of muraymycin A1 against S. aureus was highlighted by the Wyeth-Research groups. Thus, it is of our interest to validate the efficacy of muraymycin A1 in vitro and in vivo against M. tuberculosis. However, the fungus strain (Streptomyces spp. LL-AA896) used to produce muraymycin A1 and any congeners are not available, and muraymycin A1 has to be synthesized for the in vitro compound profiling. Thus, we will establish the synthetic route for intact muraymycin A1 to obtain enough molecules (Specific Aim 1). Furthermore, medicinal chemistry programs of muraymycin A1 and capuramycin with an aim to improve the efficacy including pharmacokinetics are hampered by 1) the complexity of these structures, 2) difficulty in chemically modifying the desired positions selectively, and 3) no convenient assay against Mtb MraY enzyme including difficulty in obtaining enough MraY substrate, Park's nucleotide. We accomplished a scalable chemoenzymatic and total synthesis of Park's nucleotide and its fluorescent probe, and established a convenient MraY inhibitor assay using a cell envelop enriched fraction including MraY, MurG and decaprenylphosphate. In addition, over the past years we obtained extensive knowledge of synthetic accessibility of uridine-amino-alcohol containing molecules in solution or on the polymer- support. We will continue designing and synthesizing new uridine-amino-alcohol derivatives in order to identify the minimal and essential structures of muraymycins and capuramycin (Specific Aim 2). In vitro profiling of the generated molecules against Mtb MraY and drug-sensitive and -resistant M. tuberculosis will be performed at the CSU Mycobacteria Research Laboratory (Specific Aim 3). PUBLIC HEALTH RELEVANCE: Multidrug resistant Mycobacterium tuberculosis (MDR-TB) has occurred in hospitals and correctional facilities, and frequently in HIV-infected patient. Clinical responses of MDR- TB patient to currently available drugs have been poor, and in some cases there is no response at all. The long term goal of this grant submission is to develop new drug leads for MDR-TB.

描述（由申请人提供）：来自天然来源的MRAY抑制剂，使用结核分枝杆菌小鼠感染模型在体内表现出显着的活性。 Muraymycins具有铜霉素的共同核心结构，但是，它们的结构多样性在无环的复杂二肽部分和C5'-Sugar申请中观察到。 Wyeth-Research组强调了Muraymycin A1对金黄色葡萄球菌的体内抗菌活性。因此，我们的利益是验证穆雷霉素A1在体外和体内对结核分枝杆菌的疗效。然而，真菌菌株（链霉菌属Spp。LL-AA896）用于生产穆雷霉素A1，并且任何同类物都不可用，并且必须合成Muraycin A1的体外化合物分析。因此，我们将建立完整的Muraymycin A1的合成途径以获得足够的分子（特定目标1）。此外，穆拉米霉素A1和辣椒素的药物化学计划的目的是提高包括药代动力学在内的功效，受到1）这些结构的复杂性的阻碍，2）在化学上选择性地修改所需位置的难度，以及3）对MRAY ENZYME（包括在内的MRAY中，都不是在MRAY中进行了足够的便利性分析。我们完成了PARK核苷酸及其荧光探针的可伸缩化学酶和总合成，并使用包括MRAY，MURG和DECAPRENYL磷酸盐在内的细胞包膜包裹的富集分数建立了方便的MRAY抑制剂测定。此外，在过去的几年中，我们获得了有关溶液中含有分子或聚合物载体中尿苷 - 氨基醇的合成可及性的广泛了解。我们将继续设计和合成新的尿苷 - 氨基醇衍生物，以确定穆雷米霉素和辣椒素的最低和基本结构（特定的目标2）。对MTB MRAY产生的分子的体外分析以及对药物敏感和耐药的结核分子将在CSU分枝杆菌研究实验室进行（特定的目标3）。公共卫生相关性：耐多药结核分枝杆菌（MDR-TB）发生在医院和惩教设施中，经常在HIV感染的患者中发生。 MDR-TB患者对当前可用药物的临床反应较差，在某些情况下根本没有反应。这份赠款提交的长期目标是为MDR-TB开发新药物。