Exploring statins as a small molecule therapy for treatment of schistosomiasis

描述（由申请人提供）：血吸虫病是一种由血吸虫引起的慢性、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预防艾滋病毒的优先事项。血吸虫病的治疗和控制仅依赖于吡喹酮（PZQ）一种药物。除了对可能产生耐药性的担忧外，PZQ还有许多缺点。首先，40mg /kg的标准口服剂量很少完全有效，据报道治愈率在50%至90%之间。第二，PZQ主要杀死成虫，让未成熟的寄生虫逃脱，在成熟后继续产生疾病。第三，PZQ被迅速代谢为一系列代谢物，其中只有一种代谢物具有部分活性。此外，这种药物有一种令人反感的味道

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.