Sanhan Huashi Formula and Its Bioactive Compounds Exert Antiviral and Anti-Inflammatory Effects on COVID-19
Chuanxi Tian,
Hang Liu,
Qian Wang,
Jinyue Zhao,
Chensi Yao,
Yanfeng Yao,
Xu Zhang,
Qinhai Ma,
Weihao Wang,
Yanyan Zhou,
Mengxiao Wang,
Xiaomeng Shi,
Xiangyan Li,
Shan Wang,
Yingying Yang,
Xiaowen Gou,
Lijuan Zhou,
Jingyi Zhao,
Li Wan,
Jiarui Li,
Stefanie Tiefenbacher,
Juntao Gao,
Rudolf Bauer,
Min Li,
Xiaolin Tong
Affiliations
Chuanxi Tian
Institute of Metabolic Diseases, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China; Graduate School, Beijing University of Chinese Medicine, Beijing 100029, China
Hang Liu
Center for Biosafety Mega-Science, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China
Qian Wang
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China
Jinyue Zhao
Graduate School, Changchun University of Chinese Medicine, Changchun 130117, China
Chensi Yao
Department of Endocrinology, The First Affiliated Hospital of Zhejiang Chinese Medicine University, Hangzhou 310006, China
Yanfeng Yao
Center for Biosafety Mega-Science, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China
Xu Zhang
Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China; College of Pharmacy, Hebei Medical University, Shijiazhuang 050017, China
Qinhai Ma
State Key Laboratory of Respiratory Disease & National Clinical Research Center for Respiratory Disease & Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510120, China
Weihao Wang
Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
Yanyan Zhou
Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
Mengxiao Wang
Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
Xiaomeng Shi
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China
Xiangyan Li
Graduate School, Changchun University of Chinese Medicine, Changchun 130117, China
Shan Wang
National Center for Integrative Medicine, China-Japan Friendship Hospital, Beijing 100029, China
Yingying Yang
National Center for Integrative Medicine, China-Japan Friendship Hospital, Beijing 100029, China
Xiaowen Gou
Institute of Metabolic Diseases, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
Lijuan Zhou
Institute of Metabolic Diseases, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
Jingyi Zhao
Institute of Metabolic Diseases, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
Li Wan
Institute of Metabolic Diseases, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
Jiarui Li
Graduate School, Changchun University of Chinese Medicine, Changchun 130117, China
Stefanie Tiefenbacher
Institute of Pharmaceutical Sciences, University of Graz, Graz 8010, Austria
Juntao Gao
Institute for TCM-X, MOE Key Laboratory of Bioinformatics/Bioinformatics Division, Beijing National Research Center for Information Science and Technology, Center for Synthetic & Systems Biology, Tsinghua University, Beijing 100084, China
Rudolf Bauer
Institute of Pharmaceutical Sciences, University of Graz, Graz 8010, Austria; Corresponding authors.
Min Li
Molecular Biology Laboratory, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China; Corresponding authors.
Xiaolin Tong
Institute of Metabolic Diseases, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China; Corresponding authors.
Sanhan Huashi formula (SHHS), a traditional Chinese medicine (TCM), has shown significant therapeutic effects on coronavirus disease 2019 (COVID-19) in clinical settings. However, its specific mechanism and components still require further clarification. In vitro experiments with Vero-E6 cells infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) demonstrated that SHHS effectively inhibited viral invasion and proliferation. Complementary in vivo experiments using K18-human angiotensin converting enzyme 2 (hACE2) mice exposed to virus-like particles (VLPs) further confirmed that SHHS impeded SARS-CoV-2 entry. Although SHHS did not demonstrate direct antiviral effects in K18-hACE2 mice challenged with SARS-CoV-2, it significantly alleviated pathological damage and decreased the expression of chemokines such as C–C motif ligand (CCL)-2, CCL-3, C–X–C motif ligand (CXCL)-1, CXCL-6, CXCL-9, CXCL-10, and CXCL-11 in the lungs, suggesting that SHHS exerts immunomodulatory and anti-inflammatory effects via the CCL-2–CXCL axis. Additional research using a lipopolysaccharide (LPS)-induced acute lung injury (ALI) and RAW264.7 cell model validated the ability of SHHS to reduce the levels of inflammatory biomarkers, including interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNF-α). Using advanced analytical techniques such as ultrahigh-performance liquid chromatography coupled with linear trap quadrupole Orbitrap mass spectrometry (UHPLC-LTQ-Orbitrap-MS) and surface plasmon resonance (SPR), nodakenin was identified as a potent antiviral component of SHHS that targets the 3C-like protease (3CLpro), a finding supported by the hydrogen–deuterium exchange mass spectrometry (HDX-MS) and molecular docking analyses. Furthermore, nodakenin demonstrated a significant antiviral effect, reducing the viral load by more than 66%. This investigation reveals that SHHS can combat COVID-19 by inhibiting viral invasion and promoting anti-inflammatory effects.
