Lead compounds for antimalarial chemotherapy:: Purine base analogs discriminate between human and P-falciparum 6-oxopurine phosphoribosyltransferases
Lead compounds for antimalarial chemotherapy:: Purine base analogs discriminate between human and P-falciparum 6-oxopurine phosphoribosyltransferases
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DOI：
10.1021/jm061012j
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发表时间：
2006-12-14
影响因子：
7.3
通讯作者：
de Jersey, John
中科院分区：
文献类型：
--
作者：
Keough, Dianne T.;Skinner-Adams, Tina;de Jersey, John
恶性疟原虫依赖嘌呤补救酶次黄嘌呤-鸟嘌呤-黄嘌呤磷酸核糖转移酶（HGXPRT）将宿主的嘌呤碱基转化为DNA和RNA合成所需的核苷酸。开发抗疟疾药物的一种方法是使用HGXPRT将引入的嘌呤碱基类似物转化为对寄生虫有毒的核苷酸。这种策略要求这些化合物是寄生虫酶的良好底物，但对人类对应物HGPRT来说是不良底物。在6-位具有氯原子或在8-位具有氮原子的碱基在恶性疟原虫HGXPRT和人HGPRT之间表现出强烈的区分。使用6-氯鸟嘌呤和8-氮鸟嘌呤作为底物的疟原虫酶的k（cat）/K-m值分别比人酶高50-80倍和336倍。这些和其他碱在体外有效抑制寄生虫的生长，IC 50值低至1 μ M。
The malarial parasite Plasmodium falciparum depends on the purine salvage enzyme hypoxanthine-guanine-xanthine phosphoribosyltransferase (HGXPRT) to convert purine bases from the host to nucleotides needed for DNA and RNA synthesis. An approach to developing antimalarial drugs is to use HGXPRT to convert introduced purine base analogs to nucleotides that are toxic to the parasite. This strategy requires that these compounds be good substrates for the parasite enzyme but poor substrates for the human counterpart, HGPRT. Bases with a chlorine atom in the 6-position or a nitrogen in the 8-position exhibited strong discrimination between P. falciparum HGXPRT and human HGPRT. The k(cat)/K-m values for the Plasmodium enzyme using 6-chloroguanine and 8-azaguanine as substrates were 50-80-fold and 336-fold higher than for the human enzyme, respectively. These and other bases were effective in inhibiting the growth of the parasite in vitro, giving IC50 values as low as 1 mu M.