Inhibiting tegumental carbonic anhydrase as a novel treatment for schistosomiasis

抑制皮膜碳酸酐酶作为血吸虫病的新治疗方法

• 批准号: 8682118
• 负责人: Patrick J Skelly
• 金额: $ 20.54万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-03 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8682118
• 关键词: Acetazolamide; Adolescent; Animals; Biochemistry; Biological; Biological Assay; Blood Circulation; Carbon Dioxide; Carbonic Anhydrase Inhibitors; Cessation of life; Chemicals; Chemistry; Chronic; Clinical Trials; Collection; Coumarins; Country; Development; Disease; Drug Targeting; Drug usage; Enzymes; Exhibits; Genes; Helminths; Homologous Gene; Human; Hydro-Lyases; In Vitro; Infection; Infection prevention; Inhibitory Concentration 50; Laboratories; Laboratory Study; Life; Mammalian Cell; Measures; Morbidity - disease rate; Mus; Nature; Parasites; Physiological; Platyhelminths; Praziquantel; Praziquantel resistance; Protein Isoforms; Proteins; RNA Interference; Recombinant Proteins; Recombinants; Research; Schistosoma; Schistosoma japonicum; Schistosoma mansoni; Schistosomiasis; Series; Solubility; Source; Staging; Staining method; Stains; Sulfonamides; Surface; System; Testing; Toxic effect; Vaccines; Variant; Work; World Health Organization; alpha benzopyrone; base; carbonate dehydratase; compound 30; cost; global health; in vivo; inhibitor/antagonist; killings; neglect; novel; novel therapeutics; public health relevance; sulfamate

DESCRIPTION (provided by applicant): Schistosomiasis is a serious global health problem caused by intravascular parasitic worms called schistosomes. Currently ~200 million people are infected with these parasites. Tens of millions of people have chronic morbidity and new treatments are needed. We have identified a carbonic anhydrase enzyme (SmCA) that is an accessible and rational target of such treatment. The enzyme is expressed on the surface of intravascular stage schistosomes. Parasites with diminished SmCA (achieved through RNAi) fail to establish a robust infection in mice. Chemical compounds that mimic the RNAi effect and inhibit SmCA should likewise debilitate the worms. Carbonic anhydrases (CAs) are extremely druggable proteins and several drugs that target vertebrate CA isoforms are currently used to treat a number of conditions in humans. The aim of this application is to identify potent and specific SmCA inhibitors to test the hypothesis that these can form the basis for a novel anti-schistosome therapy. We partner here with Dr. Claudiu Supuran, a world leader in carbonic anhydrases and their inhibitors. Dr. Supuran has amassed a defined, unique set of ~400 CA inhibitors and chemical variants for testing here with SmCA. To facilitate testing, we have expressed SmCA as a secreted recombinant protein in a mammalian expression system and we have purified the active enzyme from the medium. Potent SmCA inhibitors identified by Dr. Supuran will be subject to a validated secondary screen in which their ability to decrease CA activity in living parasites in vitro is measured. Here, we will test all 3 major species of human schistosome to identify pan-schistosome CA inhibitors. We believe that our approach will yield effective schistosome CA inhibitors that will debilitate the parasites and form the basis of a new and urgently needed therapy to treat schistosomiasis, a neglected, global condition that remains a source of tremendous death and morbidity in the 21st century.

描述（由申请人提供）：血吸虫病是一种严重的全球性健康问题，由血管内寄生蠕虫称为寄生虫）引起。目前约有2亿人感染了这些寄生虫。数千万人患有慢性病，需要新的治疗方法。我们已经确定了碳酸酐酶（SmCA），这是一个访问和合理的目标，这样的治疗。该酶在血管内阶段的溶酶体表面上表达。具有减少的SmCA（通过RNAi实现）的寄生虫未能在小鼠中建立稳健的感染。模拟RNA干扰效应并抑制SmCA的化合物也会使蠕虫衰弱。碳酸酐酶（CA）是一种极其可药用的蛋白质，目前有几种针对脊椎动物CA亚型的药物被用于治疗人类的多种疾病。本申请的目的是鉴定有效和特异性的SmCA抑制剂，以检验这些抑制剂可以形成新型抗肿瘤药物治疗基础的假设。我们与Claudiu Supuran博士合作，他是碳酸酐酶及其抑制剂的世界领导者。Supuran博士积累了一套定义明确的独特的约400种CA抑制剂和化学变体，用于SmCA测试。为了便于测试，我们已经表达SmCA作为一种分泌的重组蛋白在哺乳动物表达系统中，我们已经从培养基中纯化的活性酶。由Supuran博士鉴定的有效SmCA抑制剂将进行经验证的二次筛选，其中测量其在体外降低活寄生虫中CA活性的能力。在这里，我们将测试所有3种主要的人类染色体，以确定泛染色体CA抑制剂。我们相信，我们的方法将产生有效的抗寄生虫CA抑制剂，这将削弱寄生虫，并形成一个新的和迫切需要的治疗血吸虫病，一个被忽视的，全球性的条件，仍然是一个巨大的死亡和发病率在21世纪世纪的来源的基础。