University of Applied Sciences Bonn-Rhein-Sieg, Von Liebig Strasse 20, 53359, Rheinbach, Germany.
Amino Acids. 2010 Feb;38(2):471-7. doi: 10.1007/s00726-009-0406-9. Epub 2009 Dec 3.
Antimalarial drug resistance has nowadays reached each drug class on the market for longer than 10 years. The focus on validated, classical targets has severe drawbacks. If resistance is arising or already present in the field, a target-based High-Throughput-Screening (HTS) with the respective target involves the risk of identifying compounds to which field populations are also resistant. Thus, it appears that a rewarding albeit demanding challenge for target-based drug discovery is to identify novel drug targets. In the search for new targets for antimalarials, we have investigated the biosynthesis of hypusine, present in eukaryotic initiation factor 5A (eIF5A). Deoxyhypusine hydroxylase (DOHH), which has recently been cloned and expressed from P. falciparum, completes the modification of eIF5A through hydroxylation. Here, we assess the present druggable data on Plasmodium DOHH and its human counterpart. Plasmodium DOHH arose from a cyanobacterial phycobilin lyase by loss of function. It has a low FASTA score of 27 to its human counterpart. The HEAT-like repeats present in the parasite DOHH differ in number and amino acid identity from its human ortholog and might be of considerable interest for inhibitor design.
抗疟药物耐药性如今已经在市场上的每种药物类别中存在了超过 10 年。关注已验证的经典靶点存在严重的缺陷。如果耐药性在现场出现或已经存在，那么针对该靶点的基于靶标的高通量筛选 (HTS) 存在识别出现场人群也耐药的化合物的风险。因此，对于基于靶标的药物发现来说，识别新的药物靶点似乎是一项具有挑战性但有回报的任务。在寻找抗疟药物的新靶点时，我们研究了真核起始因子 5A (eIF5A) 中存在的 hypusine 的生物合成。最近已从疟原虫中克隆并表达了脱氧hypusine 羟化酶 (DOHH)，通过羟化完成了 eIF5A 的修饰。在这里，我们评估了目前关于疟原虫 DOHH 及其人类对应物的可成药性数据。疟原虫 DOHH 是由蓝藻藻胆蛋白裂解酶失去功能产生的。它与人源蛋白的 FASTA 评分仅为 27。寄生虫 DOHH 中存在的 HEAT 样重复序列在数量和氨基酸同一性上与其人类同源物不同，可能对抑制剂设计具有重要意义。
