Chen Xiaofei, Wu Yunlong, Chen Chun, Gu Yanqiu, Zhu Chunyan, Wang Suping, Chen Jiayun, Zhang Lei, Lv Lei, Zhang Guoqing, Yuan Yongfang, Chai Yifeng, Zhu Mingshe, Wu Caisheng
School of Pharmacy, Naval Medical University, Shanghai 200433, China.
Fujian Provincial Key Laboratory of Innovative Drug Target Research and State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, Xiamen 361102, China.
Acta Pharm Sin B. 2021 Jan;11(1):222-236. doi: 10.1016/j.apsb.2020.10.002. Epub 2020 Oct 10.
Lianhuaqingwen (LHQW) capsule, a herb medicine product, has been clinically proved to be effective in coronavirus disease 2019 (COVID-19) pneumonia treatment. However, human exposure to LHQW components and their pharmacological effects remain largely unknown. Hence, this study aimed to determine human exposure to LHQW components and their anti-COVID-19 pharmacological activities. Analysis of LHQW component profiles in human plasma and urine after repeated therapeutic dosing was conducted using a combination of HRMS and an untargeted data-mining approach, leading to detection of 132 LHQW prototype and metabolite components, which were absorbed the gastrointestinal tract and formed biotransformation in human, respectively. Together with data from screening by comprehensive 2D angiotensin-converting enzyme 2 (ACE2) biochromatography, 8 components in LHQW that were exposed to human and had potential ACE2 targeting ability were identified for further pharmacodynamic evaluation. Results show that rhein, forsythoside A, forsythoside I, neochlorogenic acid and its isomers exhibited high inhibitory effect on ACE2. For the first time, this study provides chemical and biochemical evidence for exploring molecular mechanisms of therapeutic effects of LHQW capsule for the treatment of COVID-19 patients based on the components exposed to human. It also demonstrates the utility of the human exposure-based approach to identify pharmaceutically active components in Chinese herb medicines.
连花清瘟胶囊是一种草药产品，临床已证明其对2019冠状病毒病（COVID-19）肺炎治疗有效。然而，人体对连花清瘟成分的暴露情况及其药理作用仍 largely未知。因此，本研究旨在确定人体对连花清瘟成分的暴露情况及其抗COVID-19的药理活性。采用高分辨率质谱（HRMS）和非靶向数据挖掘方法相结合，对重复治疗给药后人体血浆和尿液中的连花清瘟成分谱进行分析，检测到132种连花清瘟原型和代谢物成分，它们分别经胃肠道吸收并在人体内发生生物转化。结合通过全面二维血管紧张素转换酶2（ACE2）生物色谱法筛选的数据，确定了连花清瘟中8种暴露于人体且具有潜在ACE2靶向能力的成分进行进一步的药效学评价。结果表明，大黄酸、连翘酯苷A、连翘酯苷I、新绿原酸及其异构体对ACE2具有较高的抑制作用。本研究首次基于人体暴露成分，为探索连花清瘟胶囊治疗COVID-19患者的治疗作用分子机制提供了化学和生化证据。它还证明了基于人体暴露的方法在鉴定中药中具有药理活性成分方面的实用性。
