El Kouni Mahmoud H
Department of Pharmacology and Toxicology, Center for AIDS Research, Comprehensive Cancer Center, General Clinical Research Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Comp Biochem Physiol B Biochem Mol Biol. 2017 Nov;213:55-80. doi: 10.1016/j.cbpb.2017.07.001. Epub 2017 Jul 21.
Schistosomes are responsible for the parasitic disease schistosomiasis, an acute and chronic parasitic ailment that affects >240 million people in 70 countries worldwide. It is the second most devastating parasitic disease after malaria. At least 200,000 deaths per year are associated with the disease. In the absence of the availability of vaccines, chemotherapy is the main stay for combating schistosomiasis. The antischistosomal arsenal is currently limited to a single drug, Praziquantel, which is quite effective with a single-day treatment and virtually no host-toxicity. Recently, however, the question of reduced activity of Praziquantel has been raised. Therefore, the search for alternative antischistosomal drugs merits the study of new approaches of chemotherapy. The rational design of a drug is usually based on biochemical and physiological differences between pathogens and host. Pyrimidine metabolism is an excellent target for such studies. Schistosomes, unlike most of the host tissues, require a very active pyrimidine metabolism for the synthesis of DNA and RNA. This is essential for the production of the enormous numbers of eggs deposited daily by the parasite to which the granulomas response precipitates the pathogenesis of schistosomiasis. Furthermore, there are sufficient differences between corresponding enzymes of pyrimidine metabolism from the host and the parasite that can be exploited to design specific inhibitors or "subversive substrates" for the parasitic enzymes. Specificities of pyrimidine transport also diverge significantly between parasites and their mammalian host. This review deals with studies on pyrimidine metabolism in schistosomes and highlights the unique characteristic of this metabolism that could constitute excellent potential targets for the design of safe and effective antischistosomal drugs. In addition, pyrimidine metabolism in schistosomes is compared with that in other parasites where studies on pyrimidine metabolism have been more elaborate, in the hope of providing leads on how to identify likely chemotherapeutic targets which have not been looked at in schistosomes.
血吸虫是导致寄生虫病血吸虫病的病原体，这是一种急慢性寄生虫病，全球70个国家超过2.4亿人受其影响。它是仅次于疟疾的第二大致命性寄生虫病。每年至少有20万人死于该疾病。由于缺乏疫苗，化疗是对抗血吸虫病的主要手段。目前抗血吸虫病的药物仅有吡喹酮一种，该药单日治疗效果显著且几乎无宿主毒性。然而，最近有人提出吡喹酮活性降低的问题。因此，寻找替代抗血吸虫病药物值得对化疗新方法进行研究。药物的合理设计通常基于病原体与宿主之间的生化和生理差异。嘧啶代谢是此类研究的理想靶点。与大多数宿主组织不同，血吸虫需要非常活跃的嘧啶代谢来合成DNA和RNA。这对于寄生虫每天产生大量虫卵至关重要，虫卵引发的肉芽肿反应会促使血吸虫病发病。此外，宿主和寄生虫嘧啶代谢的相应酶之间存在足够差异，可利用这些差异设计针对寄生虫酶的特异性抑制剂或“颠覆性底物”。寄生虫与其哺乳动物宿主之间嘧啶转运的特异性也有显著差异。本文综述了血吸虫嘧啶代谢的研究，强调了这种代谢的独特特征，这些特征可能成为设计安全有效的抗血吸虫病药物的极佳潜在靶点。此外，还将血吸虫的嘧啶代谢与其他寄生虫的嘧啶代谢进行了比较，在其他寄生虫中，嘧啶代谢的研究更为详尽，以期为如何识别血吸虫中尚未研究过的潜在化疗靶点提供线索。
