ABSTRACT
Background Coronavirus disease 2019 (COVID-19) pandemic is still raging worldwide, while the treatment of human coronaviruses (HCoVs) infections remains limited. Qingfeipaidu decoction (QFPDD), formulated by four classical prescriptions, was the most widely used prescription for COVID-19 containment and exhibited positive effects in China. As one critical prescription in QFPDD, Xiaochaihu decoction (XCHD) could relieve the symptoms of fever, fatigue, anorexia, sore throat in TCM theory. 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 network of XCHD against HCoVs. Subsequently, multi-level systems pharmacology analyses highlighted the key regulatory proteins of XCHD, and revealed that XCHD may affect multiple biological functions related to HCoVs. We further applied network-based prediction, drug-likeness analysis, combined with literature investigation to uncover the key ani-HCoV constituents in XCHD, while in vitro HCoV-229E virus-induced cytopathic effect assay was carried out to verify our prediction. Finally, we proposed molecular mechanism hypothesis for these compounds against HCoVs via subnetwork analysis.Results Based on the systems pharmacology framework, we identified 163 XCHD constituents connecting to 37 HCoV-associated genes. And an integrated pathway comprising TLR signaling pathway, RIG-1-like receptor signaling pathway, cytoplasmic DNA sensing pathway, and IL-6/STAT3 pro-inflammatory signal transduction axis was further proposed, revealing the mechanism of action of XCHD against HCoVs. Through in vitro assay, several constituents (e.g. betulinic acid, chrysin, isoliquiritigenin, schisandrin B, and (20R)-Ginsenoside Rh1) in XCHD exerted good inhibitory activity against HCoV-229E virus.Conclusion Our work presented a comprehensive systems pharmacology approach to explore the molecular mechanism and effective substances of XCHD against HCoVs.