Exploring statins as a small molecule therapy for treatment of schistosomiasis

探索他汀类药物作为治疗血吸虫病的小分子疗法

• 批准号: 8569887
• 负责人: Conor Caffrey
• 金额: $ 18.44万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-05 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8569887
• 关键词: AIDS prevention; Abdominal Pain; Adult; Affect; Anemia; Anthelmintics; Attention; Biological Assay; Chemistry; Child; Chronic; Coenzyme A; Cognitive; Collaborations; Collection; Data; Deglutition; Development; Disease; Doctor of Philosophy; Dose; Drug Targeting; Drug resistance; Failure; Future; HIV; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Image; In Vitro; Individual; Industry; Infection; Informatics; Kinetics; Lead; Libraries; Life; Marketing; Molecular Target; Morbidity - disease rate; Oral; Oxidoreductase; Parasites; Parasitic Diseases; Parents; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Plasma; Praziquantel; Productivity; Property; Recombinants; Reporting; Research Activity; Research Personnel; Resources; Risk; Schistosoma; Schistosoma mansoni; Schistosomatidae; Schistosome Parasite; Schistosomiasis; Series; Structure; Tablets; Taste Perception; Testing; Therapeutic; Time; Vesnarinone; Whole Organism; World Health Organization; analog; cell motility; design; drug candidate; drug development; drug discovery; hypercholesterolemia; improved; in vivo; inhibitor/antagonist; innovation; killings; liver metabolism; neglect; novel; programs; public health relevance; research and development; response; screening; small molecule; technology development; tool

DESCRIPTION (provided by applicant): Schistosomiasis, caused by a blood fluke, is a chronic, morbid and 'neglected' disease affecting as many as 700 million people globally. Ensuing anemia, abdominal pain, impaired physical and cognitive development degrade individual and societal productivity. Infection also elevates the risk of acquiring HIV, making treatment of schistosomiasis a priority for HIV-prevention. Treatment and control of schistosomiasis relies on just one drug, praziquantel (PZQ). Apart from concerns over possible drug resistance, PZQ has a number of failings. First, the standard oral dose of 40 mg/kg is rarely completely effective, with reported cure rates anywhere between 50 and 90%. Second, PZQ primarily kills adult parasites allowing immature worms to escape that upon maturation go on to generate morbidity. Third, PZQ is rapidly metabolized to a series of metabolites of which only one is partially as active as the parent molecule. In addition, the drug has a repellent taste and is marketed as a large 600 mg tablet making compliance, especially for children, difficult. The World Health Organization encourages the discovery and development of new drug candidates. The UCSF Center for Discovery and Innovation in Parasitic Diseases (www.cdipd.org) has identified commercial anti-hypercholesterolemia statin drugs - inhibitors of HMG-CoA reductase (3-hydroxy-3-methyl-glutaryl-CoA reductase or HMGR) - as potent schistosomicidal compounds. Statins first came to our attention during phenotypic whole-organism screens designed specifically to identify potential therapeutics for the schistosome parasite, screens that have now been adapted to quantitative, high-content imaging platforms. In advance of a detailed structure-activity lead optimization program to develop specific anti-schistosomal statins, we propose two Specific Aims. First, in partnership with an industry leader in statin drug development (Merck Sharp & Dohme Corp. ("Merck")), we will employ quantitative and 'targeted' phenotypic screening of privileged statin libraries to obtain a preliminary understanding of the structural determinants of statin analogs that kill the parasite in vitro, including those that improve killing activity over commercial statins already tested. Secondly, we will optimize and standardize the recombinant expression of active Schistosoma mansoni HMGR, which will be central to deriving the kinetic and crystallographic data necessary to prosecute a subsequent lead optimization program to identify candidate molecules for treatment of schistosomiasis. The engagement of a large pharmaceutical company like Merck represents a watershed moment for schistosomiasis R&D since the discovery of PZQ 40 years ago. The combination of Merck's expertise in statin chemistry and UCSF's parasitological/screening expertise will short-list novel and more potent anti-schistosomal molecules. The proposed research activity is in advance of a collaborative and longer-term lead optimization program that will continue to utilize the tools employed or developed herein.

描述（由申请人提供）：血吸虫病由血吸虫引起，是一种慢性病态且“被忽视”的疾病，影响全球多达 7 亿人。随之而来的贫血、腹痛、身体和认知发育受损会降低个人和社会的生产力。感染还会增加感染艾滋病毒的风险，因此治疗血吸虫病成为预防艾滋病毒的首要任务。血吸虫病的治疗和控制仅依赖于一种药物：吡喹酮 (PZQ)。除了担心可能产生耐药性之外，PZQ 还有许多缺点。首先，40 mg/kg 的标准口服剂量很少完全有效，据报道治愈率在 50% 到 90% 之间。其次，PZQ 主要杀死成虫寄生虫，使未成熟的蠕虫逃脱，成熟后继续产生发病率。第三，PZQ 快速代谢为一系列代谢物，其中只有一种代谢物部分具有母体分子的活性。此外，该药具有驱避味道 并且以 600 毫克大片的形式销售，使得依从性（尤其是儿童）变得困难。世界卫生组织鼓励发现和开发新候选药物。加州大学旧金山分校寄生虫病发现与创新中心 (www.cdipd.org) 已确定商业抗高胆固醇血症他汀类药物 - HMG-CoA 还原酶（3-羟基-3-甲基-戊二酰-CoA 还原酶或 HMGR）抑制剂 - 是有效的杀血吸虫化合物。他汀类药物首次引起我们的注意是在表型全生物体筛选过程中，该筛选专门设计用于识别血吸虫寄生虫的潜在治疗方法，该筛选现已适应定量、高内涵成像平台。在开发特定抗血吸虫他汀类药物的详细结构活性先导物优化计划之前，我们提出了两个具体目标。首先，我们将与他汀类药物开发领域的行业领导者（Merck Sharp & Dohme Corp.（“默克”））合作，对专有他汀类药物库进行定量和“靶向”表型筛选，以初步了解体外杀死寄生虫的他汀类药物类似物的结构决定因素，包括那些比已测试的商业他汀类药物提高杀伤活性的因素。其次，我们将优化和标准化活性曼氏血吸虫 HMGR 的重组表达，这对于导出必要的动力学和晶体学数据至关重要，以执行后续的先导优化计划，以确定治疗血吸虫病的候选分子。自 40 年前发现 PZQ 以来，像默克这样的大型制药公司的参与标志着血吸虫病研发的分水岭。默克公司在他汀类药物化学方面的专业知识和加州大学旧金山分校的寄生虫学/筛选专业知识相结合，将筛选出新颖且更有效的抗血吸虫分子。拟议的研究活动是在协作和长期先导物优化计划之前进行的，该计划将继续利用本文所使用或开发的工具。