Plasmodium falciparum parasites are killed by a transition state analogue of purine nucleoside phosphorylase in a primate animal model.
Plasmodium falciparum parasites are killed by a transition state analogue of purine nucleoside phosphorylase in a primate animal model.
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DOI：
10.1371/journal.pone.0026916
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Schramm VL
中科院分区：
文献类型：
--
作者：
Cassera MB;Hazleton KZ;Merino EF;Obaldia N 3rd;Ho MC;Murkin AS;DePinto R;Gutierrez JA;Almo SC;Evans GB;Babu YS;Schramm VL
每年死于疟疾的100万人中，绝大多数是由恶性疟原虫引起的。抗药性很普遍，需要针对新靶点的新型药物来支持世界卫生组织提倡的联合治疗方法。疟原虫是嘌呤营养缺陷型。阻断嘌呤核苷磷酸化酶（PNP）通过嘌呤饥饿杀死培养的寄生虫。DADMe-Immucillin-G（BCX 4945）是人和疟原虫PNP的过渡态类似物，以皮摩尔亲和力结合。在这里，我们在Aotus灵长类动物中测试BCX 4945，这是一种恶性疟原虫感染的动物模型。口服施用BCX 4945七天导致Aotus猴中恶性疟原虫的其它致死感染中的寄生虫清除和复发。BCX 4945的分子作用在人和恶性疟原虫PNP的晶体结构中得到证实。代谢物分析表明，PNP阻断抑制嘌呤补救和多胺合成的寄生虫。BCX 4945的有效性、口服利用度、化学稳定性、独特的作用机制和低毒性证明了与这种新型抗疟剂联合治疗的潜力。
Plasmodium falciparum causes most of the one million annual deaths from malaria. Drug resistance is widespread and novel agents against new targets are needed to support combination-therapy approaches promoted by the World Health Organization. Plasmodium species are purine auxotrophs. Blocking purine nucleoside phosphorylase (PNP) kills cultured parasites by purine starvation. DADMe-Immucillin-G (BCX4945) is a transition state analogue of human and Plasmodium PNPs, binding with picomolar affinity. Here, we test BCX4945 in Aotus primates, an animal model for Plasmodium falciparum infections. Oral administration of BCX4945 for seven days results in parasite clearance and recrudescence in otherwise lethal infections of P. falciparum in Aotus monkeys. The molecular action of BCX4945 is demonstrated in crystal structures of human and P. falciparum PNPs. Metabolite analysis demonstrates that PNP blockade inhibits purine salvage and polyamine synthesis in the parasites. The efficacy, oral availability, chemical stability, unique mechanism of action and low toxicity of BCX4945 demonstrate potential for combination therapies with this novel antimalarial agent.
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DOI：
10.1073/pnas.86.2.651
发表时间：
1989-01-01
影响因子：
11.1
作者：
BITONTI, AJ;DUMONT, JA;SJOERDSMA, A
通讯作者：
SJOERDSMA, A
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
DOI：
10.1016/j.jchromb.2007.04.013
发表时间：
2007-07-01
影响因子：
3
作者：
Farthing, Don;Sica, Domenic;Karnes, H. Thomas
通讯作者：
Karnes, H. Thomas
影响因子：
2.9
作者：
Edwards, Achelle A.;Mason, Jennifer M.;Schramm, Vern L.
通讯作者：
Schramm, Vern L.
影响因子：
20.3
作者：
Balakrishnan, Kumudha;Verma, Dushyant;Ravandi, Farhad
通讯作者：
Ravandi, Farhad