Preclinical Development of Novel Rickettsiosis Therapeutics Targeting EPAC1

针对 EPAC1 的立克次体病新型疗法的临床前开发

基本信息

批准号：
8694342
负责人：
XIAODONG CHENG
金额：
$ 153.87万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-10 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8694342
关键词：
Animal Model Antibiotic Therapy Bacteria Binding Biochemical Biological Assay Biological Process Biological Warfare Biology Bioterrorism Boutonneuse Fever Breathing Categories Cell Nucleus Cell membrane Cell physiology Cells Chemicals Chloramphenicol Clinical Drug Development Collaborations Cyclic AMP Cyclic AMP Receptors Cyclic AMP-Dependent Protein Kinases Cytochrome P450 Data Development Docking Dose Drug Kinetics Early Diagnosis Eukaryotic Cell Evaluation Event Family Fatal Outcome Fever G22P1 gene General Population Genes Guanine Nucleotide Exchange Factors Human In Vitro Incidence Infection International Intracellular Second Messenger Knockout Mice Laboratories Lead Libraries Mediating Metabolic Modeling Molecular Mus National Institute of Allergy and Infectious Disease Pathogenesis Patients Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacodynamics Phenotype Physiological Play Preclinical Testing Prevention Prevention strategy Property Prophylactic treatment Proteins Reporting Research Institute Research Personnel Resistance Rickettsia Rickettsia Infections Rickettsia prowazekii Rocky Mountain Spotted Fever Role Route Safety Second Messenger Systems Signal Transduction Specificity Structure-Activity Relationship System Temperature Testing Tetracyclines Therapeutic Tick-Borne Diseases Ticks Toxic effect Treatment Efficacy Typhus Wild Type Mouse analog animal tissue base biodefense climate change design drug candidate efficacy testing genotoxicity human disease improved in vivo in vivo Model industry partner inhibitor/antagonist microbial mouse model new therapeutic target novel pathogen pre-clinical preclinical efficacy preclinical safety public health relevance receptor response small molecule therapeutic target

项目摘要

DESCRIPTION (provided by applicant): This is an R01 application in response to RFA-AI-13-013 "Partnerships for Biodefense (R01)". Rickettsioses represent some of the most devastating human infections. These tick-borne diseases are caused by obligately intracellular bacteria of the genus Rickettsia, including typhus fever (Rickettsia prowazekii), an NIAID Category B Priority pathogen. It has been forecasted that temperature increases due to global climate change will lead to more widespread incidence of rickettsioses. In addition, a high infectivity and severe illness after inhalation make rickettsiae potential bioterrorism threats. Although rickettsil infections can be controlled by appropriate broad-spectrum antibiotic therapy if diagnosed early, up to 20% of misdiagnosed or untreated and 5% of treated Rocky Mountain spotted fever (RMSF) cases result in a fatal outcome. In fact, a fatality rate as high as 32% has been reported in hospitalized patients with Mediterranean spotted fever. Strains of R. prowazekii resistant to tetracycline and chloramphenicol have been developed in laboratories. Therefore, novel mechanism-based treatments are urgently needed. Our recent studies reveal that exchange protein directly activated by cAMP (Epac1) plays an important role in rickettsiosis. Deletion of Epac1 gene in mice protects them from fatal rickettsioses. Most importantly, we have developed first-in-class, small-molecule Epac specific-inhibitors (ESIs). Using these ESIs, we have further demonstrated that pharmacological inhibition of Epac in vivo recapitulates the Epac1-null phenotype: wild-type mice treated with an ESI are protected from fatal rickettsioses. These results indicate that Epac1 is a novel therapeutic target for potentially fatal rickettsiosis. In te present proposal, we will design, synthesize and optimize the lead candidates discovered in our laboratory for the discovery and development of more potent and specific ESIs with minimal toxicity, desired pharmacokinetic (PK) and pharmacodynamic (PD) properties. Optimized ESIs will be further analyzed for preclinical testing for efficacy and safety to identify drug candidate in animal models in vivo for the development of effective therapeutics for rickettsioses.

描述（由申请人提供）：这是响应RFA-AI-13-013“ Biodefense（R01）的合作伙伴关系”的R01申请。人力体是一些最具破坏性的人类感染。这些tick传播的疾病是由立克属的细胞内细菌（包括Typhus Fever（Rickettsia prowazekii）），一种NIAID B类优先病原体引起的。人们已经预测，由于全球气候变化而导致的温度升高将导致立克索斯的发生率更广泛。另外，高感染力和吸入后的严重疾病使立克斯萨潜在的生物恐怖主义威胁。尽管可以通过适当的广谱抗生素治疗来控制立克索尔感染，如果诊断为诊断，则可以通过适当的广谱抗生素治疗，但多达20％的误诊或未经治疗的疾病，5％的落基山斑点发烧（RMSF）病例会导致致命的结果。实际上，在住院的地中海发现发烧的患者中，死亡率高达32％。在实验室中已经开发了对四环素和氯霉素的抗性菌菌的菌株。因此，迫切需要基于机制的新型治疗。我们最近的研究表明，CAMP（EPAC1）直接激活的交换蛋白在立克菌病中起重要作用。小鼠中EPAC1基因的缺失可保护它们免受致命的身份毒素的侵害。最重要的是，我们开发了一类小子EPAC特异性抑制剂（ESI）。使用这些ESI，我们进一步证明了EPAC在体内的药理学抑制作用概括了EPAC1-NULL表型：用ESI处理的野生型小鼠受到保护不受致命的立克西氏症的保护。这些结果表明，EPAC1是潜在致命的立克病的新型治疗靶标。在当前的建议中，我们将设计，合成和优化我们实验室中发现的主要候选者，以发现和开发更有效和特定的ESI，具有最小的毒性，所需的药代动力学（PK）和药物学（PD）特性。将进一步分析优化的ESI，以进行临床前测试的功效和安全性，以确定体内动物模型中的药物候选者，以开发有效的立克疾病治疗疗法。