Targeting host deubiquitinases for broad spectrum anti-infective therapy

靶向宿主去泛素酶进行广谱抗感染治疗

• 批准号: 8389503
• 负责人: Mary O'Riordan
• 金额: $ 19.44万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8389503
• 关键词: Affect; Animal Model; Anti-Infective Agents; Antiviral Agents; Bacteria; Bacteriology; Biochemistry; Biological Assay; Cantaloupes; Categories; Cells; Chemicals; Communicable Diseases; Data; Development; Diagnosis; Disease Outbreaks; Drug Kinetics; Drug resistance; Early treatment; Economics; Encephalomyocarditis virus; Enzymes; Future; Gastroenteritis; Goals; Human; In Vitro; Infection; Infection prevention; Infectious Agent; Injection of therapeutic agent; Investigational New Drug Application; La Crosse virus; Lead; Link; Listeria; Listeria monocytogenes; Liver Microsomes; Mediating; Microbe; Modeling; Molecular Weight; Morbidity - disease rate; Mus; Norovirus; Organism; Parasites; Pharmaceutical Chemistry; Pharmacology; Phase; Positioning Attribute; Proteins; Proteomics; Public Health; Research; Role; Salmonella enterica; Series; Sindbis Virus; Solubility; Structure-Activity Relationship; Testing; Therapeutic; Toxic effect; Toxoplasma gondii; Ubiquitin; Ubiquitination; United States; Vaccines; Viral Gastroenteritis; Virus; War; Water; age group; analog; antimicrobial; base; cytotoxicity; drug development; drug resistant bacteria; effective therapy; foodborne; foodborne illness; foodborne infection; foodborne pathogen; in vivo; inhibitor/antagonist; methicillin resistant Staphylococcus aureus; microbial; mortality; novel; novel therapeutics; pathogen; polypeptide; pre-clinical; programs; small molecule; therapeutic target; virology

DESCRIPTION (provided by applicant): There is an urgent need for new therapeutics to effectively target drug-resistant microbes and pathogens that currently have no treatment options. Noroviruses cause an estimated 23 million infections and over half of all food-borne gastroenteritis outbreaks in the US every year yet no antivirals or vaccines exist to treat or prevent infections. Listeria monocytogenes is another food-borne pathogen with a 20 - 25% fatality rate, responsible for recent cantaloupe-associated food-borne infection outbreaks. There is a compelling rationale for developing broad-spectrum therapeutics for early and effective treatment of infectious diseases. One approach towards that goal is development of "anti-infective" compounds that target host-encoded proteins critical during pathogen infection. Ubiquitin is a eukaryotic low molecular weight polypeptide that acts as a post-translational regulatory switch when covalently linked to target proteins. This application provides preliminary data showing a small molecule, WP1130 (WP) and related compounds have anti-infective activity against different classes of pathogens, including: category B bacteria (MRSA, Listeria monocytogenes, Salmonella enterica serovar Typhimurium); viruses (murine and human norovirus, encephalomyocarditis virus, Sindbis virus, La Crosse virus); and an apicomplexan parasite (Toxoplasma gondii). WP inhibits a subset of host cell deubiquitinases (DUBs), causing accumulation of ubiquitinated proteins. Pathogens outside the host are not affected. Studies using WP analogs provide vital clues for development of novel therapeutics that may effectively control pathogens by interfering with key host and microbe interactions. Ubiquitination and deubiquination of host targets have critical roles in many microbial infections. We hypothesize that WP can limit infection by selectively inhibiting DUBs exploited by microbial pathogens. We will use murine norovirus and L. monocytogenes and established small animal models of infection to define DUB targets that mediate the anti-infective effects of WP. Our goal is to select lead compound to be utilized in an investigational new drug (IND) application. We propose the following specific aims: (1) Determine target DUBs of WP that mediate anti-infective activity, (2) Test a SAR series of WP in vitro to identify lead compounds, and (3) Test lead compounds for in vivo efficacy. This application proposes to develop broad-spectrum anti-infective therapeutics that have efficacy against many pathogens including multiple category B agents. PUBLIC HEALTH RELEVANCE: Infectious agents are a major cause of morbidity and mortality in the United States today. The emergence of drug resistant organisms is a major public health concern. We have identified a novel compound with anti-infective activity against many microbial pathogens that include: drug-resistant bacteria; viruses; and parasites. Further study of this compound could lead to development of therapeutics that target critical cellular enzymes used by pathogens.

描述（由申请人提供）：迫切需要新的治疗方法来有效地针对目前没有治疗选择的耐药微生物和病原体。诺如病毒每年在美国造成约 2300 万例感染，占所有食源性胃肠炎爆发的一半以上，但目前尚无治疗或预防感染的抗病毒药物或疫苗。单核细胞增生李斯特氏菌是另一种食源性病原体，死亡率为 20 - 25%，是最近爆发的与哈密瓜相关的食源性感染的原因。开发广谱疗法以早期有效治疗传染病有令人信服的理由。实现这一目标的一种方法是开发“抗感染”化合物，该化合物针对病原体感染过程中至关重要的宿主编码蛋白质。 泛素是一种真核低分子量多肽，与靶蛋白共价连接时可充当翻译后调节开关。 该申请提供的初步数据显示小分子 WP1130 (WP) 和相关化合物对不同类别的病原体具有抗感染活性，包括： B 类细菌（MRSA、单核细胞增生李斯特氏菌、肠沙门氏菌鼠伤寒血清型）；病毒（鼠和人诺如病毒、脑心肌炎病毒、辛德比斯病毒、拉克罗斯病毒）；和顶端复门寄生虫（弓形虫）。 WP 抑制宿主细胞去泛素酶 (DUB) 的子集，导致泛素化蛋白的积累。 宿主外部的病原体不受影响。 使用 WP 类似物的研究为开发新型疗法提供了重要线索，这些疗法可以通过干扰关键宿主和微生物的相互作用来有效控制病原体。宿主靶标的泛素化和去泛素化在许多微生物感染中发挥着关键作用。 我们假设 WP 可以通过选择性抑制微生物病原体利用的 DUB 来限制感染。我们将使用鼠诺如病毒和单核细胞增生李斯特氏菌并建立小动物感染模型来定义介导 WP 抗感染作用的 DUB 靶点。我们的目标是选择先导化合物用于研究性新药 (IND) 应用。我们提出以下具体目标：(1) 确定 WP 介导抗感染活性的靶 DUB，(2) 体外测试 SAR 系列 WP 以鉴定先导化合物，以及 (3) 测试先导化合物的体内功效。该申请旨在开发广谱抗感染疗法，对许多病原体（包括多种 B 类药物）有效。 公共卫生相关性：传染源是当今美国发病和死亡的主要原因。 耐药微生物的出现是一个重大的公共卫生问题。我们已经鉴定出一种对许多微生物病原体具有抗感染活性的新型化合物，其中包括：耐药细菌；病毒；和寄生虫。对这种化合物的进一步研究可能会导致针对病原体使用的关键细胞酶的治疗方法的开发。