二氢乳清酸脱氢酶靶向抗疟药研究进展

疟疾是全球危害最严重的传染性疾病之一，尤其是在非洲，发病率与死亡率仍居高不下。抗药性的出现和发展使大多数现有抗疟药在临床上失去了效用，研究和开发新型抗疟药已成为当前疟疾防治研究的迫切需求。随着恶性疟原虫基因组测序的完成和对疟原虫生物学认知的不断深入，寻找抗疟新靶点的研究得以快速发展。嘧啶生物合成途径是经临床确证有效的抗疟靶点的典范。我们简要综述了近年来以恶性疟原虫嘧啶从头合成途径第四步关键酶——二氢乳清酸脱氢酶（DHODH）为靶点的抗疟新药研究。高通量筛选、药物化学等研究已获得若干对恶性疟原虫DHODH有选择性抑制作用的化合物结构，其中有些在恶性疟原虫体外培养试验中表现出了较强的抗疟作用，且其酶抑制活性与抗疟活性间具有良好的相关性。通过三唑并嘧啶类系列先导化合物的优化研究，已获得了具有良好代谢稳定性、对鼠疟模型有效的类似物。已有大量研究表明DHODH靶向抗疟药的研发具有广阔前景。

Proceedings on Dihydroorotate Dehydrogenase-Targeted Antimalarial Research

Malaria remains the one of major global health threats that leads to significant morbidity and mortali- ty, especially in Africa. The emerging and development of drug resistance has compromised most of current antima- larial drugs used clinically and made the development of new antimalarial drugs urgent. The completion of Plasmo- dium falciparum genome and growing knowledge of parasite biology are promoting the discovery of novel antimalari- al targets. The pyrimidine biosynthesis pathway illustrates one best sample of successful identification of antimalari- al drug targets. This review focused on recent efforts to explore the fourth enzyme in the de novo pyrimidine bio- synthesis pathway of P.falciparum, dihydroorotate dehydrogenase（Pj-＇DHODH）, as a new target for antimalarial drugs discovery. By high throughput screening and other methods, several chemical scaffolds have been identified as po- tent inhibitors of PfDHODH, and shown strong selectivity for malarial enzyme over its human counterpart. Some of them have also showed potent activity against P.falciparum in whole cell assay with good correlation between activi- ty on the enzyme and parasite. Lead optimization of a triazolopyrimidine-based series has sought out an analog with good metablic stability and efficacy against P.bergei infected mouse model. These data confirmed that the dis- covery and development of antimalarial agents targeting PfDHODH has a great promise.