Alkyne modified purines for assessment of activation of Plasmodium vivax hypnozoites and growth of pre-erythrocytic and erythrocytic stages in Plasmodium spp.
Alkyne modified purines for assessment of activation of Plasmodium vivax hypnozoites and growth of pre-erythrocytic and erythrocytic stages in Plasmodium spp.
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DOI：
10.1016/j.ijpara.2022.03.003
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发表时间：
2022-10
影响因子：
4
通讯作者：
Kyle, Dennis E.
中科院分区：
文献类型：
--
作者：
Botnar, Alona;Lawrence, Grant;Maher, Steven P.;Vantaux, Amelie;Witkowski, Benoit;Shiau, Justine C.;Merino, Emilio F.;De Vore, David;Yang, Christian;Murray, Cameron;Cassera, Maria B.;Leahy, James W.;Kyle, Dennis E.
疟疾是一个主要的全球健康问题，主要影响发展中国家。虽然目前有许多抗疟疾疗法，但引起这种疾病的原生动物寄生虫，疟原虫属，继续逃避根除工作。一种阻碍根除努力的生物学现象是寄生虫能够阻止发育，转化为药物不敏感的形式，然后在治疗后恢复生长。目前，寄生虫进入发育停滞或休眠，然后复发或重新激活以继续发育的机制尚不清楚，疟疾领域缺乏研究这些难以捉摸的机制的技术。由于疟原虫属（Plasmodium spp.）为了挽救嘌呤用于DNA合成，我们假设含炔的嘌呤核苷可用于开发DNA合成标记，其可用于研究休眠背后的机制。使用铜催化的点击化学方法，我们观察到炔修饰的腺苷，肌苷，次黄嘌呤的掺入在积极复制无性血液阶段的恶性疟原虫和掺入的修饰的腺苷在积极复制肝阶段的间日疟原虫。值得注意的是，这些修饰的嘌呤没有被纳入休眠的肝脏阶段催眠虫，这表明该标记物可以被用作区分复制和非复制肝脏形式的工具，更广泛地说，作为一种工具，用于推进我们对疟原虫休眠机制的理解。
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 hypothesized 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-catalyzed 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.
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影响因子：
16.6
作者：
Mok S;Stokes BH;Gnädig NF;Ross LS;Yeo T;Amaratunga C;Allman E;Solyakov L;Bottrill AR;Tripathi J;Fairhurst RM;Llinás M;Bozdech Z;Tobin AB;Fidock DA
通讯作者：
Fidock DA
影响因子：
3
作者：
Merrick CJ
通讯作者：
Merrick CJ
影响因子：
82.9
作者：
Dembele, Laurent;Franetich, Jean-Francois;Mazier, Dominique
通讯作者：
Mazier, Dominique
影响因子：
4.6
作者：
Dorjsuren D;Eastman RT;Wicht KJ;Jansen D;Talley DC;Sigmon BA;Zakharov AV;Roncal N;Girvin AT;Antonova-Koch Y;Will PM;Shah P;Sun H;Klumpp-Thomas C;Mok S;Yeo T;Meister S;Marugan JJ;Ross LS;Xu X;Maloney DJ;Jadhav A;Mott BT;Sciotti RJ;Winzeler EA;Waters NC;Campbell RF;Huang W;Simeonov A;Fidock DA
通讯作者：
Fidock DA
影响因子：
4.6
作者：
Niklaus, L.;Agop-Nersesian, C.;Heussler, V. T.
通讯作者：
Heussler, V. T.