Licorice-saponin A3 is a broad-spectrum inhibitor for COVID-19 by targeting viral spike and anti-inflammation

Yang Yi; Wenzhe Li; Kefang Liu; Heng Xue; Rong Yu; Meng Zhang; Yang-Oujie Bao; Xinyuan Lai; Jingjing Fan; Yuxi Huang; Jing Wang; Xiaomeng Shi; Junhua Li; Hongping Wei; Kuanhui Xiang; Linjie Li; Rong Zhang; Xin Zhao; Xue Qiao; Hang Yang; Min Ye

doi:10.1016/j.jpha.2023.05.011

Volume 14 Issue 1

Jan. 2024

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Article Navigation > Journal of Pharmaceutical Analysis > 2024 > 14(1): 115-127

Yang Yi, Wenzhe Li, Kefang Liu, Heng Xue, Rong Yu, Meng Zhang, Yang-Oujie Bao, Xinyuan Lai, Jingjing Fan, Yuxi Huang, Jing Wang, Xiaomeng Shi, Junhua Li, Hongping Wei, Kuanhui Xiang, Linjie Li, Rong Zhang, Xin Zhao, Xue Qiao, Hang Yang, Min Ye. Licorice-saponin A3 is a broad-spectrum inhibitor for COVID-19 by targeting viral spike and anti-inflammation[J]. Journal of Pharmaceutical Analysis, 2024, 14(1): 115-127. doi: 10.1016/j.jpha.2023.05.011

Citation:

Yang Yi, Wenzhe Li, Kefang Liu, Heng Xue, Rong Yu, Meng Zhang, Yang-Oujie Bao, Xinyuan Lai, Jingjing Fan, Yuxi Huang, Jing Wang, Xiaomeng Shi, Junhua Li, Hongping Wei, Kuanhui Xiang, Linjie Li, Rong Zhang, Xin Zhao, Xue Qiao, Hang Yang, Min Ye. Licorice-saponin A3 is a broad-spectrum inhibitor for COVID-19 by targeting viral spike and anti-inflammation[J]. Journal of Pharmaceutical Analysis, 2024, 14(1): 115-127. doi: 10.1016/j.jpha.2023.05.011

Citation:

Yang Yi, Wenzhe Li, Kefang Liu, Heng Xue, Rong Yu, Meng Zhang, Yang-Oujie Bao, Xinyuan Lai, Jingjing Fan, Yuxi Huang, Jing Wang, Xiaomeng Shi, Junhua Li, Hongping Wei, Kuanhui Xiang, Linjie Li, Rong Zhang, Xin Zhao, Xue Qiao, Hang Yang, Min Ye. Licorice-saponin A3 is a broad-spectrum inhibitor for COVID-19 by targeting viral spike and anti-inflammation[J]. Journal of Pharmaceutical Analysis, 2024, 14(1): 115-127. doi: 10.1016/j.jpha.2023.05.011

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Licorice-saponin A3 is a broad-spectrum inhibitor for COVID-19 by targeting viral spike and anti-inflammation

doi: 10.1016/j.jpha.2023.05.011

Yang Yi^a,
Wenzhe Li^a,
Kefang Liu^c,e,h,
Heng Xue^d,e,
Rong Yu^a,
Meng Zhang^a,
Yang-Oujie Bao^a,
Xinyuan Lai^f,
Jingjing Fan^a,
Yuxi Huang^a,
Jing Wang^a,
Xiaomeng Shi^a,
Junhua Li^d,e,
Hongping Wei^d,e,
Kuanhui Xiang^f,
Linjie Li^c,e,
Rong Zhang^c,e,
Xin Zhao^c,e,
Xue Qiao^a,
Hang Yang^{d,e,g
,
,},
Min Ye^{a,b
,
,}

a. State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China;
b. Yunnan Baiyao International Medical Research Center, Peking University, Beijing, 100191, China;
c. CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, 100101, China;
d. CAS Key Laboratory of Special Pathogens and Biosafety, Center for Biosafety Mega-Science, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, 430071, China;
e. University of Chinese Academy of Sciences, Beijing, 100049, China;
f. Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Peking University, Beijing, 100191, China;
g. Hubei Jiangxia Laboratory, Wuhan, 430000, China;
h. Shenzhen Children's Hospital, Shenzhen, Guangdong, 518036, China

Funds:

This work was supported by National Natural Science Foundation of China (Grant Nos.: 81891010/81891011, 81725023, 82003614, 82173950, 31770192, 32070187, 32161133003 and 82003681) and China Postdoctoral Science Foundation (Grant No: 2022T150029). We thank Professor George Fu Gao from CAS Institute of Microbiology for helpful and constructive suggestions. We also thank Tao Du, Lun Wang, Jin Xiong, and the entire running team from Zhengdian Biosafety Level 3 Laboratory of Wuhan Institute of Virology for technical support. We thank the Wroclaw Center for Networking and Super Computing for providing generous computer time, and Jingjie PTM BioLab Co., Ltd. (Hangzhou, China) for proteomics mass spectrometry analysis.

Received Date: Feb. 02, 2023
Accepted Date: May 18, 2023
Rev Recd Date: May 17, 2023
Publish Date: May 22, 2023

Abstract

Abstract

Currently, human health due to corona virus disease 2019 (COVID-19) pandemic has been seriously threatened. The coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) protein plays a crucial role in virus transmission and several S-based therapeutic approaches have been approved for the treatment of COVID-19. However, the efficacy is compromised by the SARS-CoV-2 evolvement and mutation. Here we report the SARS-CoV-2 S protein receptor-binding domain (RBD) inhibitor licorice-saponin A3 (A3) could widely inhibit RBD of SARS-CoV-2 variants, including Beta, Delta, and Omicron BA.1, XBB and BQ1.1. Furthermore, A3 could potently inhibit SARS-CoV-2 Omicron virus in Vero E6 cells, with EC₅₀ of 1.016 μM. The mechanism was related to binding with Y453 of RBD determined by hydrogen-deuterium exchange mass spectrometry (HDX-MS) analysis combined with quantum mechanics/molecular mechanics (QM/MM) simulations. Interestingly, phosphoproteomics analysis and multi fluorescent immunohistochemistry (mIHC) respectively indicated that A3 also inhibits host inflammation by directly modulating the JNK and p38 mitogen-activated protein kinase (MAPK) pathways and rebalancing the corresponding immune dysregulation. This work supports A3 as a promising broad-spectrum small molecule drug candidate for COVID-19.
- COVID-19,
- Inflammation,
- Licorice-saponin A3,
- Receptor-binding domain (RBD),
- SARS-CoV-2

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References(50)

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