Umbelliferone and eriodictyol suppress the cellular entry of SARS-CoV-2

Fang-Ju Cheng; Chien-Yi Ho; Tzong-Shiun Li; Yeh Chen; Yi-Lun Yeh; Ya-Ling Wei; Thanh Kieu Huynh; Bo-Rong Chen; Hung-Yu Ko; Chen-Si Hsueh; Ming Tan; Yang-Chang Wu; Hui-Chi Huang; Chih-Hsin Tang; Chia-Hung Chen; Chih-Yen Tu; Wei-Chien Huang

doi:10.1186/s13578-023-01070-y

Umbelliferone and eriodictyol suppress the cellular entry of SARS-CoV-2

Cell Biosci. 2023 Jun 28;13(1):118. doi: 10.1186/s13578-023-01070-y.

Authors

Fang-Ju Cheng^#^{1

2

3}, Chien-Yi Ho^#^{4

5

6}, Tzong-Shiun Li^#^{7

8}, Yeh Chen⁹, Yi-Lun Yeh^{1

2}, Ya-Ling Wei^{1

2}, Thanh Kieu Huynh^{1

2}, Bo-Rong Chen^{1

2

3}, Hung-Yu Ko¹⁰, Chen-Si Hsueh¹¹, Ming Tan², Yang-Chang Wu^{12

13

14}, Hui-Chi Huang¹⁵, Chih-Hsin Tang³, Chia-Hung Chen^{3

16

17}, Chih-Yen Tu^{3

16

17}, Wei-Chien Huang^{18

19

20

21

22}

Affiliations

¹ Center for Molecular Medicine, China Medical University Hospital, Taichung, 404, Taiwan.
² Graduate Institute of Biomedical Sciences, China Medical University, Taichung, 404, Taiwan.
³ School of Medicine, China Medical University, Taichung, 404, Taiwan.
⁴ Department of Biomedical Imaging and Radiological Science, China Medical University, Taichung, 404, Taiwan.
⁵ Division of Family Medicine, Physical Examination Center, China Medical University Hsinchu Hospital, Hsinchu, 302, Taiwan.
⁶ Department of Medical Research, China Medical University Hsinchu Hospital, Hsinchu, 302, Taiwan.
⁷ Department of Plastic Surgery, and Innovation Research Center, Show Chwan Memorial Hospital, Changhua, 500, Taiwan.
⁸ Graduate Institute of Biomedical Engineering, National Chung Hsing University, Taichung, 402, Taiwan.
⁹ Department of Food Science and Biotechnology, National Chung Hsing University, Taichung, 402, Taiwan.
¹⁰ Cognitive Science, University of California San Diego, San Diego, CA, 92093, USA.
¹¹ Taichung Girls' Senior High School, Taichung, 403, Taiwan.
¹² Chinese Medicine Research and Development Center, China Medical University Hospital, Taichung, 404, Taiwan.
¹³ Graduate Institute of Integrated Medicine, China Medical University, Taichung, 404, Taiwan.
¹⁴ Department of Medical Laboratory Science and Biotechnology, Asia University, Taichung, 413, Taiwan.
¹⁵ Department of Chinese Pharmaceutical Science and Chinese Medicine Resources, China Medical University, Taichung, 404, Taiwan.
¹⁶ Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung, 404, Taiwan.
¹⁷ Department of Respiratory Therapy, China Medical University, Taichung, 404, Taiwan.
¹⁸ Center for Molecular Medicine, China Medical University Hospital, Taichung, 404, Taiwan. whuang@mail.cmu.edu.tw.
¹⁹ Graduate Institute of Biomedical Sciences, China Medical University, Taichung, 404, Taiwan. whuang@mail.cmu.edu.tw.
²⁰ Department of Medical Research, China Medical University Hsinchu Hospital, Hsinchu, 302, Taiwan. whuang@mail.cmu.edu.tw.
²¹ Department of Medical Laboratory Science and Biotechnology, Asia University, Taichung, 413, Taiwan. whuang@mail.cmu.edu.tw.
²² Drug Development Center, China Medical University, Taichung, 404, Taiwan. whuang@mail.cmu.edu.tw.

^# Contributed equally.

Abstract

Background: Artemisia argyi (A. argyi), also called Chinese mugwort, has been widely used to control pandemic diseases for thousands of years since ancient China due to its anti-microbial infection, anti-allergy, and anti-inflammation activities. Therefore, the potential of A. argyi and its constituents in reducing the infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was investigated in this study.

Results: Among the phytochemicals in A. argyi, eriodictyol and umbelliferone were identified to target transmembrane serine protease 2 (TMPRSS2) and angiotensin-converting enzyme 2 (ACE2) proteins, the essential factors for the cellular entry of SARS-CoV-2, in both FRET-based enzymatic assays and molecular docking analyses. These two ingredients of A. argyi suppressed the infection of ACE2-expressed HEK-293 T cells with lentiviral-based pseudo-particles (Vpp) expressing wild-type and variants of SARS-CoV-2 spike (S) protein (SARS-CoV-2 S-Vpp) via interrupting the interaction between S protein and cellular receptor ACE2 and reducing the expressions of ACE2 and TMPRSS2. Oral administration with umbelliferone efficiently prevented the SARS-CoV-2 S-Vpp-induced inflammation in the lung tissues of BALB/c mice.

Conclusions: Eriodictyol and umbelliferone, the phytochemicals of Artemisia argyi, potentially suppress the cellular entry of SARS-CoV-2 by preventing the protein binding activity of the S protein to ACE2.

Keywords: ACE2; Artemisia argyi; Eriodictyol; SARS-CoV-2 variants; TMPRSS2; Umbelliferone.

Abstract

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