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

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

J Pharm Anal. 2023 May 22;14(1):115-127. doi: 10.1016/j.jpha.2023.05.011. Online ahead of print.

Authors

Yang Yi¹, Wenzhe Li¹, Kefang Liu^{2

3

4}, Heng Xue^{5

3}, Rong Yu¹, Meng Zhang¹, Yang-Oujie Bao¹, Xinyuan Lai⁶, Jingjing Fan¹, Yuxi Huang¹, Jing Wang¹, Xiaomeng Shi¹, Junhua Li^{5

3}, Hongping Wei^{5

3}, Kuanhui Xiang⁶, Linjie Li^{2

3}, Rong Zhang^{2

3}, Xin Zhao^{2

3}, Xue Qiao¹, Hang Yang^{5

3

7}, Min Ye^{1

8}

Affiliations

¹ State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, 38 Xueyuan Road, Beijing 100191, China.
² CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
³ University of Chinese Academy of Sciences, Beijing 100049, China.
⁴ Shenzhen Children's Hospital, 7019 Yitian Road, Shenzhen 518036, China.
⁵ CAS Key Laboratory of Special Pathogens and Biosafety, Center for Biosafety Mega-Science, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China.
⁶ Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Peking University, 38 Xueyuan Road, Beijing 100191, China.
⁷ Hubei Jiangxia Laboratory, Wuhan 430000, China.
⁸ Yunnan Baiyao International Medical Research Center, Peking University, 38 Xueyuan Road, Beijing 100191, China.

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 with 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 MAPK pathways and rebalancing the corresponding immune dysregulation. This work supports A3 as a promising broad-spectrum small molecule drug candidate for COVID-19.

Keywords: COVID-19; SARS-CoV-2; inflammation; licorice-saponin A3; receptor-binding domain (RBD).