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首页> 外文期刊>PLOS Neglected Tropical Diseases >An iterative process produces oxamniquine derivatives that kill the major species of schistosomes infecting humans
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An iterative process produces oxamniquine derivatives that kill the major species of schistosomes infecting humans

机译：迭代过程产生杀灭感染人类的​​主要血吸虫的氧基喹啉衍生物

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Schistosomiasis affects more than 229 million people in 78 countries of the world. The main treatment is Mass Drug Administration with praziquantel. With donations to the World Health Organization, approximately 250 million tablets of praziquantel are being administered in sub-Saharan Africa where about 90% of the cases of schistosomiasis occur. The concern with a monotherapy is the development of drug resistance. The need for new drugs with a different mode of action to be used in combination with praziquantel is great. In this regard, we have taken oxamniquine, a drug that was previously used to treat Schistosoma mansoni but was ineffective against S. haematobium and S. japonicum, and determined the enzyme responsible for activation of oxamniquine as a sulfotransferase. With this knowledge and the sulfotransferase crystal structure, we were able to determine the mode of action of the drug and develop an iterative approach of soaking oxamniquine derivatives into sulfotransferase crystals, determining structure function relationships, synthesizing new derivatives and testing them in an in vitro killing assay. The most effective derivatives are soaked into new crystals and the process repeated. We have identified two derivatives, CIDD-0072229 and CIDD-149830 that will kill S. haematobium and S. japonicum in addition to S. mansoni. CIDD-149830 will kill 100% of the worms of all three species within 7 days.
机译：血吸虫病在世界78个国家影响超过2.29亿人。主要治疗是吡喹酮的大规模药物施用。随着世界卫生组织的捐款，在撒哈拉以南非洲施用约2.5亿片普拉齐亚庭，其中血吸虫病的约90％发生。单药治疗的关注是耐药性的发展。需要与Praziquantel组合使用不同作用模式的新药物的需求。在这方面，我们已经服用了氧基喹啉，该药物以前用于治疗血吸虫麦森的药物，但对S.血厕所和S.Paemonicum无效，并确定了负责激活氧化氧基苯胺作为砜的酶。通过这种知识和磺基转移酶晶体结构，我们能够确定药物的作用方式，并使浸泡氧基衍生物浸泡成磺基转移酶晶体的迭代方法，确定结构功能关系，合成新衍生物并在体外杀死中测试它们。测定。最有效的衍生物被浸泡成新的晶体并重复该过程。除了S. Mansoni之外，我们已经确定了两种衍生物，CIDD-0072229和CIDD-149830，除了S. Mansoni之外，还将杀死S. haematobium和S.paponicum。 CIDD-149830将在7天内杀死所有三种物种的100％蠕虫。

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