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: 8891354
• 负责人: Mary O'Riordan
• 金额: $ 46.5万
• 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 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8891354
• 关键词: Affect; Animal Model; Anti-Infective Agents; Antiviral Agents; Bacteria; Bacteriology; Biochemistry; Biological Assay; Cantaloupes; Categories; Cells; Chemicals; Communicable Diseases; Development; Diagnosis; Disease Outbreaks; Drug Kinetics; Drug resistance; Early treatment; Economics; Encephalomyocarditis virus; Enzymes; Exhibits; 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; Play; 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; cellular targeting; 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; rapid diagnosis; small molecule; therapeutic development; therapeutic target; virology

There is an urgent need for new therapeutics that 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 but no antivirals or vaccines exist to treat or prevent infections. Listeria monocytogenes is another food-borne pathogen with a high fatality rate of 20- 25%, responsible for the recent cantaloupe-associated outbreak. Rapid diagnosis of a specific pathogen during outbreaks is often challenging. Thus, there is a compelling rationale for the development of broad-spectrum therapeutics for early and effective treatment of infectious diseases. One approach towards that goal is to develop “anti- infective” compounds that target host-encoded proteins critical during infection of multiple microbes. We find that a small molecule, WP1130 (WP) and related compounds, exhibit anti-infective activity against multiple classes of pathogens, including several category B pathogens: 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). Our initial studies demonstrate that WP inhibits a subset of host deubiquitinases (DUBs) resulting in the accumulation of ubiquitinated proteins in cells, but does not directly affect pathogens outside the host. Ubiquitin is a eukaryotic low molecular weight polypeptide that acts as a post-translational regulatory switch when covalently linked to target proteins. Studies of WP analogs hold vital clues for the development of novel therapeutics that may effectively contain pathogens by interfering with key interactions between host and microbe. Ubiquitination and deubiquination of host targets play critical roles in many different microbial infections. We therefore hypothesize that WP treatment selectively inhibits key DUBs exploited by microbial pathogens, thereby limiting infection. We will use murine norovirus and L. monocytogenes as two unrelated pathogens with established small animal models of infection to define DUB targets that mediate the anti-infective effects of WP. Our goal is to advance the lead compound towards an investigational new drug (IND) application. We therefore 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 aims to develop a broad-spectrum anti-infective therapeutic effective against many pathogens including multiple category B agents.

迫切需要有效针对耐药性的新疗法 目前没有治疗选择的微生物和病原体。诺如病毒会导致 估计有 2300 万人感染，占所有食源性胃肠炎爆发的一半以上 美国每年都会出现这种情况，但没有抗病毒药物或疫苗可以治疗或预防感染。 单核细胞增生李斯特氏菌是另一种食源性病原体，死亡率高达 20- 25%，是最近与哈密瓜相关的疫情爆发的原因。快速诊断 爆发期间的特定病原体通常具有挑战性。因此，有一个令人信服的 开发早期有效的广谱疗法的基本原理 治疗传染病。实现这一目标的一种方法是开发“反 感染性”化合物，针对宿主编码的蛋白质，这些蛋白质在感染过程中至关重要 多种微生物。我们发现一个小分子，WP1130（WP）和相关的 化合物，对多种病原体表现出抗感染活性，包括 几种 B 类病原体：细菌（MRSA、单核细胞增生李斯特菌、沙门氏菌 鼠伤寒肠血清型）、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 apicomplexan 寄生虫（弓形虫）。我们的初步研究表明 WP 抑制一个子集 宿主去泛素酶 (DUB) 导致泛素化蛋白在体内积累 细胞，但不直接影响宿主体外的病原体。泛素是一种真核生物 低分子量多肽，在以下情况下充当翻译后调节开关： 与目标蛋白共价连接。 WP 类似物的研究为 开发可通过干扰有效遏制病原体的新疗法 宿主和微生物之间的关键相互作用。泛素化和去泛素化 宿主靶点在许多不同的微生物感染中发挥着关键作用。我们因此 假设 WP 治疗选择性抑制关键 DUB 微生物病原体，从而限制感染。我们将使用鼠诺如病毒和 L. 单核细胞增生李斯特菌作为两种不相关的病原体，并建立了小动物模型 感染来确定介导 WP 抗感染作用的 DUB 靶点。我们的目标是 推进先导化合物的研究性新药 (IND) 应用。 因此，我们提出以下具体目标： (1) 确定 WP 的目标 DUB 介导抗感染活性，(2) 体外测试 SAR 系列 WP 以识别铅 化合物，以及(3)测试先导化合物的体内功效。该应用程序旨在 开发一种对多种病原体有效的广谱抗感染疗法 包括多个B类代理商。