Sanhan Huashi Formula and Its Bioactive Compounds Exert Antiviral and Anti-Inflammatory Effects on COVID-19

Engineering ›› 2024, Vol. 43 ›› Issue (12) : 159 -172. DOI: 10.1016/j.eng.2024.07.007

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^aInstitute of Metabolic Diseases, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China

^bGraduate School, Beijing University of Chinese Medicine, Beijing 100029, China

^cCenter for Biosafety Mega-Science, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China

^dState Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China

^eGraduate School, Changchun University of Chinese Medicine, Changchun 130117, China

^fDepartment of Endocrinology, The First Affiliated Hospital of Zhejiang Chinese Medicine University, Hangzhou 310006, China

^gInstitute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China

^hCollege of Pharmacy, Hebei Medical University, Shijiazhuang 050017, China

ⁱState 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

^jNational Center for Integrative Medicine, China-Japan Friendship Hospital, Beijing 100029, China

^kInstitute of Pharmaceutical Sciences, University of Graz, Graz 8010, Austria

^lInstitute 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

^mMolecular Biology Laboratory, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China

^* rudolf.bauer@uni-graz.at (R. Bauer),

^* limin-72114@163.com (M. Li),

^* tongxiaolin@vip.163.com (X. Tong).

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Received	Accepted	Published
2024-02-21	2024-07-01	2024-12-01
Issue Date	Revised Date
2024-07-01	2024-06-29

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Abstract

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 (3CL^pro), 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.

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Keywords

Sanhan Huashi formula / Coronavirus disease 2019 / Anti-inflammatory properties / Nodakenin / 3C-like protease

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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. Sanhan Huashi Formula and Its Bioactive Compounds Exert Antiviral and Anti-Inflammatory Effects on COVID-19. Engineering, 2024, 43(12): 159-172 DOI:10.1016/j.eng.2024.07.007