Saeftel Michael, Sarite Ramadan Salem, Njuguna Tujo, Holzgrabe Ulrike, Ulmer Daniela, Hoerauf Achim, Kaiser Annette
Institute for Medical Microbiology, Immunology and Parasitology, D-53105, Bonn, Germany.
Parasitol Res. 2006 Aug;99(3):281-6. doi: 10.1007/s00436-006-0173-4. Epub 2006 Mar 21.
The increasing resistance of the malaria parasites has enforced new strategies of finding new drug targets. We have isolated two genes involved in spermidine metabolism, encoding deoxyhypusine synthase (DHS) and eukaryotic initiation factor 5A (eIF-5A) in the malaria parasites. eIF-5A is activated by the formation of the unusual amino acid hypusine. This process occurs in two steps. DHS transfers an aminobutyl moiety from the triamine spermidine to a specific lysine residue in the eIF-5A precursor protein to form deoxyhypusine. In a second step, deoxyhypusine hydroxylase (DHH), completes hypusine biosynthesis. We used DHH inhibitors, being effective in mammalian cells, to study an antiplasmodicidal effect in Plasmodium falciparum. Experiments with the antifungal drug ciclopiroxolamine, an alpha-hydroxypyridone, and the plant amino acid L: -mimosine, a 4-pyridone, resulted in an antiplasmodial effect in vitro. Using mimosine as a lead structure, alkyl 4-oxo-piperidine 3-carboxylates were found to have the most efficient antiplasmodial effects in vitro and in vivo.
疟原虫耐药性的不断增加促使人们寻找新的药物靶点的新策略。我们在疟原虫中分离出了两个参与亚精胺代谢的基因，它们分别编码脱氧hypusine合酶（DHS）和真核生物起始因子5A（eIF-5A）。eIF-5A通过形成特殊氨基酸hypusine而被激活。这个过程分两步进行。DHS将来自三胺亚精胺的氨丁基部分转移到eIF-5A前体蛋白中的一个特定赖氨酸残基上，形成脱氧hypusine。在第二步中，脱氧hypusine羟化酶（DHH）完成hypusine的生物合成。我们使用在哺乳动物细胞中有效的DHH抑制剂，来研究其对恶性疟原虫的抗疟效果。使用抗真菌药物环吡酮胺（一种α-羟基吡啶酮）和植物氨基酸L-含羞草碱（一种4-吡啶酮）进行的实验，在体外产生了抗疟效果。以含羞草碱为先导结构，发现烷基4-氧代哌啶-3-羧酸盐在体外和体内具有最有效的抗疟效果。
