Honeysuckle (Lonicera japonica) and Huangqi (Astragalus membranaceus) Suppress SARS-CoV-2 Entry and COVID-19 Related Cytokine Storm in Vitro

Yuan-Chieh Yeh; Ly Hien Doan; Zi-Yi Huang; Li-Wei Chu; Tzu-Hau Shi; Ying-Ray Lee; Cheng-Tao Wu; Chao-Hsiung Lin; Shu-Tuan Chiang; Hui-Kang Liu; Tsung-Hsien Chuang; Yueh-Hsin Ping; Hsiao-Sheng Liu; Chi-Ying F Huang

doi:10.3389/fphar.2021.765553

Honeysuckle (Lonicera japonica) and Huangqi (Astragalus membranaceus) Suppress SARS-CoV-2 Entry and COVID-19 Related Cytokine Storm in Vitro

Front Pharmacol. 2022 Mar 25:12:765553. doi: 10.3389/fphar.2021.765553. eCollection 2021.

Authors

Yuan-Chieh Yeh^{1

2}, Ly Hien Doan^{3

4}, Zi-Yi Huang^{2

5}, Li-Wei Chu⁶, Tzu-Hau Shi⁷, Ying-Ray Lee^{8

9}, Cheng-Tao Wu¹⁰, Chao-Hsiung Lin^{3

7

11}, Shu-Tuan Chiang¹², Hui-Kang Liu^{13

14}, Tsung-Hsien Chuang^{15

16}, Yueh-Hsin Ping^{6

17}, Hsiao-Sheng Liu^{18

19

20}, Chi-Ying F Huang^{2

3

21

22

23}

Affiliations

¹ Department of Traditional Chinese Medicine, Chang Gung Memorial Hospital, Keelung, Taiwan.
² Program in Molecular Medicine, College of Life Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan.
³ Institute of Biopharmaceutical Sciences, College of Pharmaceutical Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan.
⁴ Institute of Biotechnology, Vietnam Academy of Science and Technology, Hanoi, Vietnam.
⁵ ASUS Intelligent Cloud Services, Taipei, Taiwan.
⁶ Department and Institute of Pharmacology, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.
⁷ Department of Life Sciences and Institute of Genome Sciences, College of Life Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan.
⁸ Department of Medical Research, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi, Taiwan.
⁹ Department of Microbiology and Immunology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
¹⁰ Division of Big Data, Phalanx Biotech Group, Hsinchu, Taiwan.
¹¹ Aging and Health Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan.
¹² Chuang Song Zong Pharmaceutical Co., Ltd. Ligang Plant, Pingtung, Taiwan.
¹³ National Research Institute of Chinese Medicine (NRICM), Ministry of Health and Welfare, Taipei, Taiwan.
¹⁴ Ph. D. Program in the Clinical Drug Development of Herbal Medicine, Taipei Medical University, Taipei, Taiwan.
¹⁵ Immunology Research Center, National Health Research Institutes, Miaoli, Taiwan.
¹⁶ Program in Environmental and Occupational Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
¹⁷ Institute of Biophotonics, College of Biomedical Science and Engineering, National Yang Ming Chiao Tung University, Taipei, Taiwan.
¹⁸ Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
¹⁹ Center for Cancer Research, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
²⁰ M.Sc. Program in Tropical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
²¹ Institute of Clinical Medicine, College of Medicine, National Yang Ming Chiao Tung, Taipei, Taiwan.
²² Department of Biotechnology and Laboratory Science in Medicine, School of Biomedical Science and Engineering, National Yang Ming Chiao Tung, Taipei, Taiwan.
²³ Department of Biochemistry, School of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.

Abstract

COVID-19 is threatening human health worldwide but no effective treatment currently exists for this disease. Current therapeutic strategies focus on the inhibition of viral replication or using anti-inflammatory/immunomodulatory compounds to improve host immunity, but not both. Traditional Chinese medicine (TCM) compounds could be promising candidates due to their safety and minimal toxicity. In this study, we have developed a novel in silico bioinformatics workflow that integrates multiple databases to predict the use of honeysuckle (Lonicera japonica) and Huangqi (Astragalus membranaceus) as potential anti-SARS-CoV-2 agents. Using extracts from honeysuckle and Huangqi, these two herbs upregulated a group of microRNAs including let-7a, miR-148b, and miR-146a, which are critical to reduce the pathogenesis of SARS-CoV-2. Moreover, these herbs suppressed pro-inflammatory cytokines including IL-6 or TNF-α, which were both identified in the cytokine storm of acute respiratory distress syndrome, a major cause of COVID-19 death. Furthermore, both herbs partially inhibited the fusion of SARS-CoV-2 spike protein-transfected BHK-21 cells with the human lung cancer cell line Calu-3 that was expressing ACE2 receptors. These herbs inhibited SARS-CoV-2 M^pro activity, thereby alleviating viral entry as well as replication. In conclusion, our findings demonstrate that honeysuckle and Huangqi have the potential to be used as an inhibitor of SARS-CoV-2 virus entry that warrants further in vivo analysis and functional assessment of miRNAs to confirm their clinical importance. This fast-screening platform can also be applied to other drug discovery studies for other infectious diseases.

Keywords: COVID-19; Huangqi; SARS-CoV-2; honeysuckle; let-7a; miR-148b; microRNA; mir-146a.