新型CYP3A4荧光探针的构建及在模拟失重环境CYP3A4活性响应规律研究中的应用

航天员在轨任务期间主要依靠药物干预提供医疗保障。CYP3A4作为关键药物代谢酶，其活性水平会直接影响相关药物的有效性和安全性。研究表明，空间失重会对多种代谢酶造成显著影响。因此，探究失重条件下CYP3A4活性响应规律，对于指导航天合理、安全用药具有重要意义。由于业界长期缺乏高灵敏、实时监测复杂生物体系CYP3A4活性的检测方法，极大阻碍了CYP3A4活性的原位精准评估。本项目拟采用计算机辅助设计和实验手段相结合策略，探究CYP3A4底物结构与酶催化选择性/效率关系规律，并基于此开发适用于复杂生物体系检测CYP3A4活性的实用型荧光探针；同时构建地基模拟失重生物模型，利用上述荧光工具分子探究模拟失重条件下CYP3A4活性响应规律，在此基础上，进一步探究CYP3A4药物代谢能力特征及药物对CYP3A4调节作用规律。上述研究可为基于CYP3A4代谢角度指导航天相关药物合理、安全使用提供科学依据。

Pharmaceutical intervention is the most important part of medical care for astronauts during space missions. As we all known, CYP3A4 is recognized as a key drug metabolizing enzyme, and the alterations of its enzymatic activity would directly impact the efficacy and safety of related drug use. In addition, studies have demonstrated that variety of metabolic enzymes could be dramatically affected by the exposure to weightlessness. Therefore, it is of great significance to investigate the response characteristics of CYP3A4 enzymatic activity in weightlessness for guiding rational and safe drug use during spaceflight. However, the highly sensitive, and real-time dynamic methods for detecting CYP3A4 activity in complex biological systems are rarely reported so far, which greatly hindering the accurate and in situ evaluation of CYP3A4 enzymatic activity. Hence, this project aimed to explore the relationship between the substrate structure and catalytic selectivity/efficiency of CYP3A4 by adopting the strategy combined computer-aided virtual design with experimental screening, which study will theoretically facilitate further development of practical fluorescent probe for monitoring CYP3A4 activity in complicated biosystems. Simultaneously, terrestrial simulated weightlessness biological model was established, and the fluorescent tool was subsequently employed for exploring the response characteristics of CYP3A4 enzymatic activity of the above-mentioned weightlessness biological model. Further, the metabolic capability of CYP3A4 for relevant drugs and the law of drugs regulating activity of CYP3A4 in the simulated weightlessness biological model were seriously evaluated. Taken together, these studies will be great helpful for providing scientific evidences for guiding rational and safe drug use during space missions from the perspective of CYP3A4 metabolism.