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靶向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，但目前还没有抗病毒药物或疫苗来治疗或预防感染。单核细胞增生李斯特菌是另一种食源性病原体，致死率为20 - 25%，是最近香瓜相关食源性感染爆发的原因。有一个令人信服的理由，发展广谱疗法的早期和有效的治疗传染病。实现该目标的一种方法是开发“抗感染”化合物，其靶向病原体感染期间关键的宿主编码蛋白质。 泛素是一种真核生物低分子量多肽，当与靶蛋白共价连接时充当翻译后调节开关。 本申请提供了显示小分子WP 1130（WP）和相关化合物对不同种类的病原体具有抗感染活性的初步数据，所述病原体包括：B类细菌（MRSA、单核细胞增生李斯特菌、鼠伤寒沙门氏菌血清型）;病毒（鼠和人诺如病毒、脑心肌炎病毒、辛德毕斯病毒、拉克罗斯病毒）;和顶复门寄生虫（刚地弓形虫）。 WP抑制宿主细胞去泛素化酶（DUB）的一个子集，导致泛素化蛋白的积累。 宿主外的病原体不受影响。 使用WP类似物的研究为开发新的疗法提供了重要线索，这些疗法可以通过干扰关键的宿主和微生物相互作用来有效地控制病原体。宿主靶标的泛素化和去泛素化在许多微生物感染中具有关键作用。 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L。单核细胞增多症和建立感染的小动物模型，以确定介导WP抗感染作用的DUB靶标。我们的目标是选择用于研究性新药（IND）申请的先导化合物。我们提出了以下具体目标：（1）确定介导抗感染活性的WP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。本申请提出开发广谱抗感染治疗剂，其对包括多种B类试剂的许多病原体具有功效。 公共卫生相关性：传染性病原体是当今美国发病率和死亡率的主要原因。 抗药性微生物的出现是一个重大的公共卫生问题。我们已经确定了一种新的化合物，对许多微生物病原体具有抗感染活性，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开发针对病原体使用的关键细胞酶的治疗方法。