Licorice-saponin A3 is a broad-spectrum inhibitor for COVID-19 by targeting viral spike and anti-inflammationOA北大核心
Licorice-saponin A3 is a broad-spectrum inhibitor for COVID-19 by targeting viral spike and anti-inflammation
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 pM.The mechanism was related to binding with Y453 of RBD deter-mined by hydrogen-deuterium exchange mass spectrometry(HDX-MS)analysis combined with quan-tum 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)path-ways and rebalancing the corresponding immune dysregulation.This work supports A3 as a promising broad-spectrum small molecule drug candidate for COVID-19.
Yang Yi;Yuxi Huang;Jing Wang;Xiaomeng Shi;Junhua Li;Hongping Wei;Kuanhui Xiang;Linjie Li;Rong Zhang;Xin Zhao;Xue Qiao;Wenzhe Li;Hang Yang;Min Ye;Kefang Liu;Heng Xue;Rong Yu;Meng Zhang;Yang-Oujie Bao;Xinyuan Lai;Jingjing Fan
State Key Laboratory of Natural and Biomimetic Drugs,School of Pharmaceutical Sciences,Peking University,Beijing,100191,ChinaCAS Key Laboratory of Special Pathogens and Biosafety,Center for Biosafety Mega-Science,Wuhan Institute of Virology,Chinese Academy of Sciences,Wuhan,430071,China||University of Chinese Academy of Sciences,Beijing,100049,ChinaDepartment of Microbiology and Infectious Disease Center,School of Basic Medical Sciences,Peking University Health Science Center,Peking University,Beijing,100191,ChinaCAS Key Laboratory of Pathogen Microbiology and Immunology,Institute of Microbiology,Chinese Academy of Sciences,Beijing,100101,China||University of Chinese Academy of Sciences,Beijing,100049,ChinaCAS Key Laboratory of Special Pathogens and Biosafety,Center for Biosafety Mega-Science,Wuhan Institute of Virology,Chinese Academy of Sciences,Wuhan,430071,China||University of Chinese Academy of Sciences,Beijing,100049,China||Hubei Jiangxia Laboratory,Wuhan,430000,ChinaState Key Laboratory of Natural and Biomimetic Drugs,School of Pharmaceutical Sciences,Peking University,Beijing,100191,China||Yunnan Baiyao International Medical Research Center,Peking University,Beijing,100191,ChinaCAS Key Laboratory of Pathogen Microbiology and Immunology,Institute of Microbiology,Chinese Academy of Sciences,Beijing,100101,China||University of Chinese Academy of Sciences,Beijing,100049,China||Shenzhen Children's Hospital,Shenzhen,Guangdong,518036,China
COVID-19InflammationLicorice-saponin A3Receptor-binding domain(RBD)SARS-CoV-2
《药物分析学报（英文）》 2024 (001)
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This work was supported by National Natural Science Founda-tion 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.(Hang-zhou,China)for proteomics mass spectrometry analysis.
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