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. 2023 Jul 20;23(1):252.
doi: 10.1186/s12906-023-04024-6.

Systems pharmacology dissection of pharmacological mechanisms of Xiaochaihu decoction against human coronavirus

Lvjie Xu #  1   2   3 , Chuipu Cai #  4   5 , Jiansong Fang  5 , Qihui Wu  5 , Jun Zhao  1   2 , Zhe Wang  1   2 , Pengfei Guo  1   2 , Lishu Zheng  6   7 , Ailin Liu  8   9
Affiliations

Systems pharmacology dissection of pharmacological mechanisms of Xiaochaihu decoction against human coronavirus

Lvjie Xu et al. BMC Complement Med Ther. .

Abstract

Background: Although coronavirus disease 2019 (COVID-19) pandemic is still rage worldwide, there are still very limited treatments for human coronaviruses (HCoVs) infections. Xiaochahu decoction (XCHD), which is one of the traditional Chinese medicine (TCM) prescriptions in Qingfeipaidu decoction (QFPDD), is widely used for COVID-19 treatment in China and able to relieve the symptoms of fever, fatigue, anorexia, and sore throat. To explore the role and mechanisms of XCHD against HCoVs, we presented an integrated systems pharmacology framework in this study.

Methods: We constructed a global herb-compound-target (H-C-T) network of XCHD against HCoVs. Multi-level systems pharmacology analyses were conducted to highlight the key XCHD-regulated proteins, and reveal multiple HCoVs relevant biological functions affected by XCHD. We further utilized network-based prediction, drug-likeness analysis, combining with literature investigations to uncover the key ani-HCoV constituents in XCHD, whose effects on anit-HCoV-229E virus were validated using cytopathic effect (CPE) assay. Finally, we proposed potential molecular mechanisms of these compounds against HCoVs via subnetwork analysis.

Results: Based on the systems pharmacology framework, we identified 161 XCHD-derived compounds interacting with 37 HCoV-associated proteins. An integrated pathway analysis revealed that the mechanism of XCHD against HCoVs is related to TLR signaling pathway, RIG-I-like receptor signaling pathway, cytoplasmic DNA sensing pathway, and IL-6/STAT3 pro-inflammatory signaling pathway. Five compounds from XCHD, including betulinic acid, chrysin, isoliquiritigenin, schisandrin B, and (20R)-Ginsenoside Rh1 exerted inhibitory activity against HCoV-229E virus in Huh7 cells using in vitro CPE assay.

Conclusion: Our work presented a comprehensive systems pharmacology approach to identify the effective molecules and explore the molecular mechanism of XCHD against HCoVs.

Keywords: HCoV-229E virus; Human coronavirus; Molecular mechanism; Systems pharmacology; Xiaochaihu decoction.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Schematic of the systems pharmacology infrastructure for uncovering the molecular mechanism of XCHD against HCoVs
Fig. 2
Fig. 2
HCoV-associated target distribution of various herbs in XCHD. Blue bars represent the number of targets for each herb, red bars represent the number of targets covered by single or multiple herbs, the dots indicate the targets associated by the ingredients in the corresponding herbs
Fig. 3
Fig. 3
Network construction of XCHD against HCoVs. A A global herb-compound-target (H-C-T) network for XCHD. For demonstration purposes, only nodes with degree larger than 20 are displayed. The labels of the top 20 targets and compounds with highest degrees are displayed. B A specific compound-target (C-T) network of XCHD against HCoVs. The node size is proportional to degree. Chemical scaffold clustering analysis of the 161 XCHD constituents targeting to HCoV-associated genes (C) and the center chemical structures (D)
Fig. 4
Fig. 4
Protein–protein interaction (PPI) of HCoVs-associated targets acted by XCHD. A PPI network. Nodes represent targets and edges represent the interactions among targets. The color brightness and the size of nodes are proportional to degree. B Degrees of the targets in the PPI network
Fig. 5
Fig. 5
Gene enrichment analysis of the HCoVs-associated host targets of XCHD. A GO terms annotation; (B) KEGG pathway enrichment; (C) Target-pathway network
Fig. 6
Fig. 6
Integrated pathway of XCHD against HCoVs
Fig. 7
Fig. 7
The C-T subnetwork and chemical structures of five active compounds in XCHD against HCoVs
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