日本血吸虫硫氧还蛋白谷胱甘肽还原酶(SjTGR)成靶性确认与基于该酶的抗血吸虫病药物先导化合物的发现

Schistosomiasis is identified to be the most neglected tropical disease by WHO. Praziquantel has been the only drug for the treatment of schistosomiasis during last 40 years and drug resistance has been generated due to years using of such unique compound. Furthermore, rational design of anti-schistosomiasis. lead compounds is undoubtedly hindered by unclear praziquantel action mechanism and lack of useful target. Therefore, it is very urgent to find new target and discover novel drug for anti-schistosomiasis. The thioredoxin glutathione reductase (TGR) is a very important enzyme for the survival of Schistosoma japonicum and it is almost no report for its using in design of new drug in china. Herein, we firstly hypothesize that TGR of Schistosoma japonicum (SjTGR) should be the target, which will be used for rational design of novel N-oxide heterocyclic compounds and the isostere derivatives of furoxan with the aid of computer in this project. Secondly, we will study structure-activity relationship between compounds structure and bioactivity (both enzyme inhibiton activity to SjTGR and bioactivity of anti-schistosome) in order to confirm the possibility of SjTGR as a new target. Thirdly，we will discover the new leads for anti-schistosomiasis based on the SjTGR. Overall, this study will supply the theoretical basis to make the SjTGR as the new target and provide a novel idea for the discovery and development of drug for anti-schistosomiasis with SjTGR as drug target.

血吸虫病是WHO确定的最被忽视的、重点防治的热带病之一。吡喹酮是40年来治疗血吸虫病的唯一药物，多年过分依赖吡喹酮单一药物治疗，已经产生药物抗性，而且，迄今尚未阐明吡喹酮作用机制，也无明确的靶标用于合理设计抗血吸虫先导化合物，严重制约了抗血吸虫新药的研发。 因此 急需寻找靶标、开发抗血吸虫新药。以日本血吸虫生长所需的重要酶-硫氧还蛋白谷胱甘肽还原酶（SjTGR）为靶标，研发抗血吸虫新药在国内基本无人研究。本项目将先假定SjTGR为靶标，进行计算机辅助的优化设计，设计合成有潜在酶抑制活性的氮氧偶极杂环新化合物和furoxan的电子等排新衍生物，其次通过化合物结构-酶活性-杀虫生物活性的构效研究，反向探索和确认SjTGR为新靶标的可能性，并以此发现以SjTGR为靶标的抗血吸虫病先导化合物。该研究将为SjTGR成靶性提供理论依据，为以SjTGR为靶标设计的抗血吸虫病药物研发提供新的思路。