Development of an effective therapy against post-exposure Anthrax

开发针对暴露后炭疽病的有效疗法

基本信息

批准号：
7480298
负责人：
Maurizio Pellecchia
金额：
$ 114.78万
依托单位：
SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-08-01 至 2011-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7480298
关键词：
Active Sites Adenylate Cyclase Adverse effects Affect Affinity Alveolar Macrophages Anthrax disease Anthrax exposure Antibiotics Antigens Apoptosis Appendix Architecture Bacillus anthracis Bacillus anthracis spore Bacteria Bacterial Antibiotic Resistance Benchmarking Biochemical Biochemistry Biological Biological Assay Bioterrorism Blood Blood Circulation Breathing Calmodulin Cell Death Cell model Cells Cessation of life Chemicals Chemistry Cipro Class Cleaved cell Collaborations Color Combined Antibiotics Communicable Diseases Complement Complex Computing Methodologies Cutaneous Cytosol Data Development Diagnosis Disease Drug Design Drug Formulations Drug Interactions Endopeptidases Engineering Enzymatic Biochemistry Enzymes Epidemic Evaluation Exotoxins Family Figs - dietary Fluorescence Resonance Energy Transfer Gastrointestinal tract structure Goals Human Human body In Vitro Individual Infection Inflammatory Institutes Kinetics Laboratories Lead Letters Ligands Matrix Metalloproteinases Metalloproteases Mitogen-Activated Protein Kinase Kinases Modeling Molecular NMR Spectroscopy Oral Organism Patients Peptide Hydrolases Peptides Pharmaceutical Chemistry Pharmaceutical Preparations Phase I Clinical Trials Phosphorylation Play Principal Investigator Process Property Prophylactic treatment Proteins Proteolysis Publications Publishing Purpose Recovery Research Research Personnel Research Project Grants Research Proposals Resolution Respiratory System Roentgen Rays Role Route Scientist Shapes Shock Signal Pathway Signal Transduction Signaling Protein Site Skin Stream Structure Techniques Testing Therapeutic Time Toxic effect Toxicology Toxin Treatment Efficacy Vaccines Virulence Factors Work anthrax lethal factor anthrax toxin base biodefense chemical synthesis design disorder control drug development edema factor efficacy evaluation experience improved in vivo inhibitor/antagonist iterative design lymph nodes macrophage member mouse model novel prevent programs response retinal rods structural biology therapy development three dimensional structure tool

项目摘要

DESCRIPTION (provided by applicant): Development of an effective therapy against post-exposure Anthrax. Anthrax is an infectious disease caused by the bacterium Bacillus anthracis. This rod shaped bacterium infects humans through the respiratory system, skin, or digestive tract. Dependent upon the entry route into the human body, Anthrax can be highly lethal. Although cutaneous Anthrax is rarely lethal, inhalation Anthrax is dangerous and usually fatal. Upon inhalation, the Anthrax spores adhere to the alveolar macrophages and germinate. Bacteria migrate to the lymph node, in which they rapidly multiply and excrete a tripartite exotoxin comprised of protective antigen (PA), lethal factor (LF, a Zn2+ dependant metalloproteinase) and calmodulin-activated edema factor adenylate cyclase (EF). The combined actions of these proteins constitute the Anthrax toxin which induces cell death particularly in macrophages by the action of LF. Once in the cytosol, LF is able to cleave several members of the MAPKK family near their N-terminus preventing interaction with, and phosphorylation of, downstream MAPKs, thereby inhibiting one or more signaling pathways. High liter of the bacteria and concomitant high level of LF in the blood stream will lead to the death of the host organism. Therefore, the developments of treatments that include a combination of antibiotics with orally active, potent, safe and selective LF inhibitors should provide an efficacious countermeasure to post-exposure Anthrax. Our three specific aims are: (I) To increase, through iterative optimizations selectivity, potency and drug-likeness of selected LF inhibitors. (II) To perform in vitro and in cell toxicity studies to refine hits and identify drug-like inhibitor(s) of LF for subsequent in vivo studies. (Ill) To perform in vivo efficacy evaluations and necessary formulation, PK and toxicity studies. Relevance Inhalation Anthrax is the most deadly form of this disease. After infection, Anthrax spores are engulfed by alveolar macrophages where germinate to generate the bacteria, which spread through the lymph nodes to the bloodstream, eventually leading to systemic fatal shock presumably due to the action of the secreted Anthrax toxin. LF (lethal factor) is a key component of the secreted toxin and plays a major role in inducing apoptosis (cell-death) of macrophages by cleaving the specific human cell signaling proteins. Our plan is to develop potent, safe, selective and orally active compounds that inhibit LF, which should prevent macrophage cell-death and promote termination of the disease. Such inhibitors will be tested as single agents and in combination with antibiotics, in order to develop the most efficacious post-exposure therapy that should facilitate and assure the recovery of patients who harbor the disease.

描述（由申请人提供）：开发针对暴露后炭疽病的有效疗法。炭疽是由炭疽杆菌引起的一种传染病。该棒形细菌通过呼吸系统，皮肤或消化道感染了人类。依靠进入人体的进入途径，炭疽病可能是高度致命的。尽管皮肤炭疽很少致死，但吸入炭疽是危险的，通常是致命的。吸入后，炭疽孢子会粘附在肺泡巨噬细胞上并发芽。细菌迁移到淋巴结，其中它们迅速繁殖并排泄由保护性抗原（PA），致死因子（LF，Zn2+依赖性金属蛋白酶）和钙调蛋白激活蛋白激活的水肿因素腺苷酸因子腺苷酸链酸蛋白酶环酸环化酶（EF）组成的三方外毒素。这些蛋白质的综合作用构成了炭疽毒素，该毒素诱导细胞死亡，尤其是通过LF的作用在巨噬细胞中。一旦进入细胞质，LF就能在其N末端附近裂解MAPKK家族的几个成员，从而防止与下游MAPKS的相互作用和磷酸化，从而抑制一种或多种信号通路。高升的细菌和伴随的血液中LF含量将导致宿主有机体的死亡。因此，包括抗生素与口服，有效，安全和选择性的LF抑制剂结合的处理的发展应为暴露后炭疽病提供有效的对策。我们的三个具体目的是：（i）通过迭代优化的选择性，效力和类似LF抑制剂的毒品来增加。（ii）在体外和细胞毒性研究中进行精炼并鉴定出LF的药物样抑制剂，以进行体内研究。（生病）进行体内功效评估和必要的表述，PK和毒性研究。相关吸入炭疽是该疾病最致命的形式。感染后，炭疽孢子被肺泡巨噬细胞吞没，在该肺泡发芽以产生细菌，这些细菌通过淋巴结传播到血液中，最终导致全身性致命休克，可能是由于分泌的炭疽毒素的作用。 LF（致命因子）是分泌毒素的关键组成部分，并且通过裂解特定的人类细胞信号蛋白来诱导巨噬细胞的凋亡（细胞死亡）中起主要作用。我们的计划是开发抑制LF的有效，安全，选择性和口服活性的化合物，以防止巨噬细胞死亡并促进疾病的终止。为了开发最有效的暴露后疗法，该抑制剂将作为单个药物和抗生素结合进行测试，以促进并确保恢复怀有这种疾病的患者。