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：
7257820
负责人：
Maurizio Pellecchia
金额：
$ 113.84万
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/7257820
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）：针对暴露后炭疽病的有效疗法的开发。炭疽病是一种由炭疽杆菌引起的传染病。这种杆状细菌通过呼吸系统、皮肤或消化道感染人类。根据进入人体的途径，炭疽病可能具有高度致命性。虽然皮肤炭疽很少致命，但吸入炭疽是危险的，通常是致命的。吸入后，炭疽孢子粘附在肺泡巨噬细胞上并发芽。细菌迁移到淋巴结，在淋巴结中快速繁殖并分泌由保护性抗原（PA）、致死因子（LF，一种 Zn2+ 依赖性金属蛋白酶）和钙调素激活的水肿因子腺苷酸环化酶（EF）组成的三联外毒素。这些蛋白质的联合作用构成了炭疽毒素，它通过 LF 的作用诱导细胞死亡，特别是在巨噬细胞中。一旦进入细胞质，LF 就能够在其 N 末端附近裂解 MAPKK 家族的多个成员，从而防止与下游 MAPK 的相互作用和下游 MAPK 的磷酸化，从而抑制一种或多种信号传导途径。高升的细菌和随之而来的血液中高水平的 LF 将导致宿主生物体的死亡。因此，开发包括抗生素与口服活性、强效、安全和选择性 LF 抑制剂组合在内的治疗方法，应该为暴露后炭疽病提供有效的对策。我们的三个具体目标是： (I) 通过迭代优化来提高所选 LF 抑制剂的选择性、效力和药物相似性。 (II) 进行体外和细胞毒性研究，以精炼命中结果并鉴定 LF 的药物样抑制剂，用于后续体内研究。 (III) 进行体内功效评价和必要的制剂、PK和毒性研究。相关性吸入性炭疽是这种疾病中最致命的形式。感染后，炭疽孢子被肺泡巨噬细胞吞噬，在肺泡巨噬细胞中发芽产生细菌，这些细菌通过淋巴结传播到血液中，最终可能由于分泌的炭疽毒素的作用而导致全身性致命性休克。 LF（致死因子）是分泌毒素的关键成分，通过裂解特定的人类细胞信号蛋白，在诱导巨噬细胞凋亡（细胞死亡）方面发挥着重要作用。我们的计划是开发有效、安全、选择性和口服活性的抑制 LF 的化合物，这应该可以防止巨噬细胞死亡并促进疾病的终止。此类抑制剂将作为单一药物和与抗生素联合进行测试，以开发最有效的暴露后疗法，以促进和确保患有该疾病的患者康复。