Identifying potential anti-COVID-19 pharmacological components of traditional Chinese medicine Lianhuaqingwen capsule based on human exposure and ACE2 biochromatography screening

  • Acta Pharm Sin B. 2021 Jan;11(1):222-236. doi: 10.1016/j.apsb.2020.10.002.
Xiaofei Chen  1 ,  Yunlong Wu  2 ,  Chun Chen  3 ,  Yanqiu Gu  3 ,  Chunyan Zhu  2 ,  Suping Wang  2 ,  Jiayun Chen  2 ,  Lei Zhang  1 ,  Lei Lv  4 ,  Guoqing Zhang  4 ,  Yongfang Yuan  3 ,  Yifeng Chai  1 ,  Mingshe Zhu  5 ,  Caisheng Wu  2
Affiliations
  • 1. School of Pharmacy, Naval Medical University, Shanghai 200433, China.
  • 2. 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.
  • 3. Department of Pharmacy, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University, Shanghai 201999, China.
  • 4. Department of Pharmacy, Shanghai Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai 200438, China.
  • 5. MassDefect Technologies, Princeton, NJ 08540, USA.
PMID: 33072499 DOI: 10.1016/j.apsb.2020.10.002
Abstract

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 via the gastrointestinal tract and formed via 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.

Keywords
ACE2; ACE2, angiotensin-converting enzyme 2; AT2, alveolar type II; Biochromatography; COVID-19; COVID-19, corona virus disease 2019; Comprehensive 2D analysis; DMF, N,N-dimethylformamide; DMSO, dimethyl sulfoxide; ESI, electrospray ionization; GMBS, N-(4-maleimide butyryl oxide)succinimide; HPLC, high performance liquid chromatography; HRMS, high resolution mass spectrometry; In vivo exposure; LHQW, Lianhuaqingwen; Lianhuaqingwen capsule; MPTS, mercaptopropyltrimethoxysilane; Molecular docking; NMPA, National Medical Products Administration; PATBS; PATBS, precise-and-thorough background-subtraction; RAS, renin–angiotensin system; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; SPR, surface plasmon resonance; Surface plasma response; TCM, traditional Chinese medicine; TIC, total ion chromatography; TOF/MS, time-of-flight mass spectrometry; ddMS2, data dependent tandem mass spectrometry 2.
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