PDF(Pubmed)
Abstract：
Malaria is a major global health problem which predominantly afflicts developing countries. Although many antimalarial therapies are currently available, the protozoan parasite causing this disease, Plasmodium spp., continues to evade eradication efforts. One biological phenomenon hampering eradication efforts is the parasite\'s ability to arrest development, transform into a drug-insensitive form, and then resume growth post-therapy. Currently, the mechanisms by which the parasite enters arrested development, or dormancy, and later recrudesces or reactivates to continue development, are unknown and the malaria field lacks techniques to study these elusive mechanisms. Since Plasmodium spp. salvage purines for DNA synthesis, we hypothesised that alkyne-containing purine nucleosides could be used to develop a DNA synthesis marker which could be used to investigate mechanisms behind dormancy. Using copper-catalysed click chemistry methods, we observe incorporation of alkyne modified adenosine, inosine, and hypoxanthine in actively replicating asexual blood stages of Plasmodium falciparum and incorporation of modified adenosine in actively replicating liver stage schizonts of Plasmodium vivax. Notably, these modified purines were not incorporated in dormant liver stage hypnozoites, suggesting this marker could be used as a tool to differentiate replicating and non-replicating liver forms and, more broadly, as a tool for advancing our understanding of Plasmodium dormancy mechanisms.
摘要：
疟疾是主要困扰发展中国家的重大全球健康问题。尽管目前有许多抗疟疗法，导致这种疾病的原生动物寄生虫，疟原虫。,继续逃避根除努力。一个阻碍根除努力的生物现象是寄生虫阻止发展的能力，转化为药物不敏感的形式，然后在治疗后恢复生长。目前,寄生虫进入停滞发育的机制，或休眠，后来重生或重新激活以继续发展，是未知的，疟疾领域缺乏技术来研究这些难以捉摸的机制。因为疟原虫。用于DNA合成的补救嘌呤，我们假设含炔的嘌呤核苷可用于开发DNA合成标记，该标记可用于研究休眠机制。使用铜催化的点击化学方法，我们观察到炔烃修饰的腺苷的掺入，肌苷,和次黄嘌呤在积极复制恶性疟原虫的无性血液阶段和在积极复制间日疟原虫的肝脏阶段分裂中掺入修饰的腺苷。值得注意的是,这些修饰的嘌呤没有被纳入休眠期的肝脏中，表明该标记可用作区分复制和非复制肝脏形式的工具，更广泛地说，作为促进我们对疟原虫休眠机制的理解的工具。
