类异戊二烯化合物生物合成的非甲羟戊酸途径是顶复合器亚门原虫等病原体所必需的生化代谢通路，已被证实是抗疟原虫、弓形虫和巴贝西虫等的有效靶点。非甲羟戊酸途径靶向抗原虫新药研究有望获得新型高效、低毒的抗原虫新药，为解决目前抗原虫药物存在毒副作用大、药效低下及原虫抗药性问题提供新的思路。然而，原虫非甲羟戊酸途径靶向抑制剂高通量筛选技术尚未见有文献报道。基于传统原虫全细胞或动物感染模型的药物筛选、评价技术无法解决活性化合物的靶向筛选问题，本课题拟建立原虫非甲羟戊酸途径关键酶-Dxs、Dxr的抑制剂高通量筛选技术方法，为寻找可能存在的非磷胺霉素相关活性结构提供高效的技术手段，同时以遗传学操作技术较为成熟的伯氏疟原虫为模型，建立异源Dxs、Dxr基因互补拯救系统，提供活性化合物的靶向明确提供全细胞和动物模型筛选、评价方法，最终为非甲羟戊酸途径靶向抗原虫新药研究的发展提供高效、可靠的药理技术平台。

The non-mevalonate or 1-Deoxy-D- xylulose -5-phospahte (DOXP) pathway of isoprenoids biosynthesis is essential for the Apicomplexa, and is an established target for anti-Plasmodium, -Toxoplasma and -Babesia. Discovery of non-mevalonate pathway targeted antiprotozoal drug will contribute greatly to the protozoan-infection control. However, the techniques for high-through screening of non-mevalonate pathway inhibitor have still not been reported. The drug-screening based on whole-cell assay and parasite-infected animals can not answer that which is the target of hits from screening. This proposal plans to establish high-through screening technique for inhibitor targeting the key enzyme in non-mevalonate pathway, such as DOXP synthase(Dxs) and DOXP reductase(Dxr), and heterogeneous complement rescued Dxs-/Dxr- Plasmodium berghei for non-mevalonate pathway targeting inhibitors screening and evaluating. Ultimately, there will be an efficient and reliable pharmacological technology platform for non-mevalonate pathway targeted antiprotozoal drug development.