Exploring statins as a small molecule therapy for treatment of schistosomiasis

描述（由申请人提供）：血吸虫病，由血吸虫引起，是一种慢性、病态和“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。感染也增加了感染艾滋病毒的风险，使血吸虫病的治疗成为艾滋病毒预防的优先事项。血吸虫病的治疗和控制仅依赖于一种药物，吡喹酮（PZQ）。除了对可能的耐药性的担忧，PZQ还有一些缺点。首先，40 mg/kg的标准口服剂量很少完全有效，报告的治愈率在50%至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被迅速代谢为一系列代谢物，其中只有一种与母体分子的活性部分相同。此外，该药物有一种令人厌恶的味道 并且作为600 mg的大片剂销售，这使得依从性，特别是对于儿童，变得困难。世界卫生组织鼓励发现和开发新的候选药物。加州大学旧金山分校寄生虫疾病发现和创新中心（www.cdipd.org）已经确定了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-作为有效的杀寄生虫化合物。他汀类药物首次引起我们的注意是在表型全有机体筛选过程中，该筛选专门用于识别寄生虫的潜在治疗方法，现在已经适用于定量，高内容的成像平台。在详细的结构-活性先导优化计划以开发特异性抗α-染色体他汀类药物之前，我们提出了两个特定目标。首先，与他汀类药物开发的行业领导者（Merck Sharp & Dohme Corp.（“Merck”））合作，我们将对特权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，包括那些提高杀死活性的商业他汀类药物。其次，我们将优化和标准化的重组表达的活性血吸虫曼氏HMGR，这将是核心的动力学和晶体学数据，进行后续的铅优化程序，以确定治疗血吸虫病的候选分子。像默克这样的大型制药公司的参与代表了自40年前发现PZQ以来血吸虫病研发的分水岭时刻。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，将筛选出新的和更有效的抗溶酶体分子。拟议的研究活动是在一个合作和长期的铅优化计划，将继续利用本文所采用或开发的工具之前。

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.