Targeting host deubiquitinases for broad spectrum anti-infective therapy

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。据估计，诺如病毒每年导致2300万人感染，美国每年爆发的食源性胃肠炎疫情中有一半以上，但目前还没有治疗或预防感染的抗病毒药物或疫苗。单核细胞增多性李斯特菌是另一种食源性致病菌，致死率为20%-25%，是最近哈密瓜相关食源性感染暴发的原因。有一个令人信服的理由来开发广谱疗法来早期和有效地治疗传染病。实现这一目标的一种方法是开发“抗感染”化合物，针对病原体感染过程中至关重要的宿主编码蛋白。泛素是一种真核小分子多肽，当与靶蛋白共价连接时，可作为翻译后调节开关。本申请提供的初步数据显示，小分子WP1130(WP)及其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、李斯特菌、沙门氏菌、鼠伤寒沙门氏菌)；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)；以及顶复合体寄生虫(弓形虫)。WP抑制宿主细胞脱泛素酶(DUBS)的一个子集，导致泛素化蛋白的积累。寄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，这些疗法可能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起着关键作用。 我们假设WP可以通过选择性地抑制微生物病原体利用的DUBS来限制感染。我们将使用小鼠诺如病毒和单核细胞增多性乳杆菌，并建立小动物感染模型，以确定介导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新药(IND)。我们提出了以下具体目标：(1)确定介导抗感染活性的WP的靶标；(2)在体外测试一系列WP的SAR以鉴定先导化合物；(3)测试先导化合物的体内有效性。本申请建议开发广谱抗感染疗法，对包括多种B类药物在内的多种病原体有效。

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.