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：
9250048
负责人：
XIAODONG CHENG
金额：
$ 120.96万
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/9250048
关键词：
Animal Model Animals Antibiotic Therapy Bacteria Binding Biochemical Biological Assay Biological Process Biological Products 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 Evolution Family Fatal Outcome Fatality rate 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 Pathologic Patients Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacodynamics Pharmacology Phenotype Physiological Play Preclinical Testing Prevention Prevention strategy Property Prophylactic treatment Proteins Reporting Research Institute Research Personnel Rickettsia Rickettsia Infections Rickettsia prowazekii Rickettsiales Rocky Mountain Spotted Fever Role Route Safety Second Messenger Systems Signal Transduction Specificity Structure-Activity Relationship System Temperature Testing Tetracycline Resistance Therapeutic Tick-Borne Diseases Ticks Tissues Toxic effect Treatment Efficacy Typhus Wild Type Mouse analog 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 novel therapeutics pathogen pre-clinical preclinical development 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“生物防御伙伴关系 (R01)”的 R01 申请。立克次体病是最具破坏性的人类感染之一。这些蜱传疾病是由立克次体属的专性细胞内细菌引起的，包括斑疹伤寒（普氏立克次体），一种 NIAID B 类优先病原体。据预测，全球气候变化导致的气温升高将导致立克次体病的更广泛发病。另外，传染性强，吸入立克次体后病情严重，使其具有潜在的生物恐怖主义威胁。尽管如果及早诊断，立克次尔感染可以通过适当的广谱抗生素治疗来控制，但高达 20% 的误诊或未经治疗以及 5% 的治疗落基山斑疹热 (RMSF) 病例会导致致命结果。事实上，据报道，住院的地中海斑疹热患者的死亡率高达 32%。实验室已培育出对四环素和氯霉素具有抗性的普瓦泽基立克氏菌菌株。因此，迫切需要新的基于机制的治疗方法。我们最近的研究表明，由 cAMP (Epac1) 直接激活的交换蛋白在立克次体病中发挥着重要作用。小鼠体内 Epac1 基因的缺失可以保护它们免受致命的立克次体病的侵害。最重要的是，我们开发了一流的小分子 Epac 特异性抑制剂 (ESI)。使用这些 ESI，我们进一步证明 Epac 体内的药理学抑制重现了 Epac1 缺失表型：用 ESI 治疗的野生型小鼠可以免受致命的立克次体病的影响。这些结果表明 Epac1 是潜在致命立克次体病的新治疗靶点。在目前的提案中，我们将设计、合成和优化我们实验室发现的主要候选药物，以发现和开发更有效、更特异性的 ESI，并具有最小的毒性、所需的药代动力学 (PK) 和药效 (PD) 特性。将进一步分析优化的 ESI，以进行临床前功效和安全性测试，以确定体内动物模型中的候选药物，从而开发有效的立克次体病治疗方法。