Development of improved fosmidomycin derivates

在疟疾寄生虫恶性疟原虫中，类异戊二烯通过1-脱氧-D-木酮糖5-磷酸（DOXP）途径合成，这在人类中是不存在的。在一项临床概念验证研究中，DOXP还原异构酶（DXR）抑制剂福司米多霉素被证明具有强效抗疟活性。然而，磷霉素不能选择性地对抗疟原虫中的DXR，但也能抑制多种细菌物种中的DXR。因此，需要使用基于结构的方法开发对恶性疟原虫DXR更特异的新DXR抑制剂。对E. coliDXR将用于建立恶性疟原虫高度同源DXR的结构模型。

In the malaria parasite Plasmodium falciparum, isoprenoid are synthesised via the 1-deoxy-D-xylulose 5-phosphate (DOXP) pathway which is absent in humans. In a clinical proof-of-concept study fosmidomycin, an inhibitor of DOXP reductoisomerase (DXR), was demonstrated to possess potent antimalarial activity. However, fosmidomycin does not act selectively against DXR in malaria parasites but also inhibits the DXR in a variety of bacterial species. Therefore, new DXR inhibitors which are more specific for P. falciparum DXR need to be developed using a structure-based approach. The available crystal structure of E. coli DXR will be used to create a structural model of the highly homologous DXR from P. falciparum.