青蒿内含增效组分协同促青蒿素抗疟活性的机制研究

基于青蒿素的联合疗法是当前对抗疟疾最有效的方式。然而，目前恶性疟原虫已对青蒿素产生耐药性。本课题组前期研究发现：青蒿酸、青蒿乙素、东莨菪内酯等青蒿内含增效组分（SCIAaL）本身并无明显的抗疟活性，却能协同显著增强青蒿素的抗疟活性。推测SCIAaL促青蒿素抗疟活性可能基于以下两种协同机制：1. SCIAaL可能抑制青蒿素的自身诱导代谢，从而逆转了自身诱导代谢所致的青蒿素体内浓度下降；2. SCIAaL可能竞争性阻断了疟原虫胞内转运子与青蒿素的结合，抑制了疟原虫对青蒿素的外排，增加了青蒿素的胞内浓度，从而降低了疟原虫对青蒿素的耐受性。本项目拟深入探讨青蒿素及SCIAaL的协同代谢谱，系统研究恶性疟原虫对青蒿素耐药性的分子机制。鉴于中药与天然产物在抗药性产生方面较化学药的优势，本研究结果将有助于发展新的截疟策略，为疟疾治疗提供新靶标，最终为开发低耐药的基于青蒿素的新型抗疟组合物奠定基础。

Artemisinin-based combination therapies (ACTs) are now the most effective anti-malarial method. However, plasmodium falciparum has been currently reported to be resistant to artemisinin. It was found in our previous studies that synergistic components included in Artemisia annua L. (SCIAaL, including artemisinic acid, arteannuin B and scopoletin) themselves showed no significant anti-malarial activities, but they could significantly strengthen the anti-malarial activity of artemisinin. Therefore, it is speculated that the synergistic effects of SCIAaL on the anti-malarial activity of artemisinin might base on the following two synergistic mechanisms: 1. SCIAaL might inhibit the auto-induced metabolism of artemisinin, then reverse the decreased concentration of artemisinin in vivo; 2. SCIAaL might also block the bindings of intracellular transporters and artemisinin, inhibit the efflux of artemisinin from plasmodium, then increase the intracellular concentration of artemisinin, and finally decrease the resistance of plasmodium to artemisinin. In present study, the synergistic metabolic profiling of artemisinin and its SCIAaL will be investigated in-depth, and the molecular mechanism of artemisinin resistance in plasmodium falciparum will also be systematically studied. In view of the incomparable superiorities of traditional Chinese medicine and natural products in the field of drug resistance to the chemical medicines, the current research results will be helpful to the development of new anti-malarial strategy, provide new targets for the treatment of malaria, and ultimately provide the foundation for the development of new artemisinin-based anti-malarial compositions with low drug resistance.