Exploring statins as a small molecule therapy for treatment of schistosomiasis

描述(申请人提供)：血吸虫病由血缘关系引起，是一种慢性、病态和被忽视的疾病，影响着全球多达7亿人。随之而来的贫血、腹痛、身体和认知发展受损会降低个人和社会生产力。感染还会增加感染艾滋病毒的风险，使血吸虫病的治疗成为预防艾滋病毒的优先事项。血吸虫病的治疗和控制仅依靠一种药物--吡喹酮(PZQ)。除了对可能的耐药性的担忧外，PZQ还有许多缺陷。首先，标准口服剂量40毫克/公斤很少是完全有效的，据报道治愈率在50%到90%之间。其次，PZQ主要杀死成虫，让未成熟的寄生虫在成熟后逃脱，从而产生发病率。第三，PZQ被迅速代谢成一系列代谢物，其中只有一种的活性部分与母体分子相同。此外，这种药物有一种令人厌恶的味道 并以600毫克大片的形式销售，这使得遵守规定变得困难，特别是对儿童来说。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病发现和创新中心(www.cdipd.org)已经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-戊二酰辅酶A还原酶或HMGR)的抑制剂-是有效的血吸虫杀灭化合物。他汀类药物第一次引起我们的注意是在专门为确定血吸虫寄生虫潜在疗法而设计的表型全生物筛查期间，这些筛查现在已经被适应于定量、高含量的成像平台。在开发抗血吸虫特异性他汀类药物的详细结构-活性先导优化程序之前，我们提出了两个具体目标。首先，我们将与他汀类药物开发的行业领先者(默克·夏普·多姆公司(Merck Sharp&Dohme Corp.)(“默克”))合作，对特权他汀库进行定量和“靶向”表型筛选，以初步了解在体外杀死寄生虫的他汀类类似物的结构决定因素，包括那些比已经测试的商业他汀类药物更具杀伤力的类似物。其次，我们将优化和标准化活性曼氏血吸虫HMGR的重组表达，这将是获得动力学和结晶学数据的核心，这些数据将进行后续的先导优化计划，以确定治疗血吸虫病的候选分子。默克这样的大型制药公司的参与代表着自40年前发现PZQ以来血吸虫病研发的分水岭时刻。默克公司在他汀类化学方面的专业知识与加州大学旧金山分校的寄生虫学/筛查专业知识相结合，将入围新的、更有效的抗血吸虫分子名单。拟议的研究活动是在合作和长期的领导优化计划之前进行的，该计划将继续利用在此使用或开发的工具。

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.