Discovery and characterization of the covalent SARS-CoV-2 3CLpro inhibitors from Ginkgo biloba extract via integrating chemoproteomic and biochemical approaches.

BACKGROUND: The 3C-like proteases (3CLpros) are cysteine-rich homodimeric proteins and can be covalently modified by numerous natural and synthetic compounds, which in turn, block the proteolytic activity or the formation of enzymatically active dimeric forms. Although herbal medicines have been widely used to treat COVID-19, identification of the key herbal constituents that can covalently modify the 3CLpros in ß-coronaviruses (CoVs) remains a big challenge. AIMS: To construct a comprehensive approach for efficient discovering the covalent SARS-CoV-2 3CLpro inhibitors from herbal medicines. To decipher the key anti-SARS-CoV-2 3CLpro constituents in Ginkgo biloba extract 50 (GBE50) and to study their anti-SARS-CoV-2 3CLpro mechanisms. METHODS: SARS-CoV-2 3CLpro inhibition assay including time-dependent inhibition assays and inactivation kinetic analyses were conducted using a fluorescence-based biochemical assay. The constituents in GBE50 were analyzed by UHPLC-Q-Exactive Orbitrap HRMS. The peptides modified by herbal constituents were characterized by using nanoLC-MS/MS. RESULTS: Following testing the anti-SARS-CoV-2 3CLpro effects of 104 herbal medicines, it was found that Ginkgo biloba extract 50 (GBE50) potently inhibited SARS-CoV-2 3CLpro in dose- and time-dependent manners. A total of 38 constituents were identified from GBE50 by UHPLC-Q-Exactive Orbitrap HRMS, while 26 peptides modified by 18 constituents were identified by chemoproteomic profiling. The anti-SARS-CoV-2 3CLpro effects of 18 identified covalent inhibitors were then validated by performing time-dependent inhibition assays. The results clearly demonstrated that most tested constituents showed time-dependent inhibition on SARS-CoV-2 3CLpro, while gallocatechin and sciadopitysin displayed the most potent anti-SARS-CoV-2 3CLpro effects. CONCLUSION: Collectively, GBE50 and some constituents in this herbal product could strongly inhibit SARS-CoV-2 3CLpro in dose- and time-dependent manner. Gallocatechin and sciadopitysin were identified as potent SARS-CoV-2 3CLpro inhibitors, which offers promising lead compounds for the development of novel anti-SARS-CoV-2 drugs.

Discovery and characterization of the covalent SARS-CoV-2 3CLpro inhibitors from Ginkgo biloba extract via integrating chemoproteomic and biochemical approaches

Background : The 3C-like proteases (3CLpros) are cysteine-rich homodimeric proteins and can be covalently modified by numerous natural and synthetic compounds, which in turn, block the proteolytic activity or the formation of enzymatically active dimeric forms. Although herbal medicines have been widely used to treat COVID-19, identification of the key herbal constituents that can covalently modify the 3CLpros in β-coronaviruses (CoVs) remains a big challenge. Aims : To construct a comprehensive approach for efficient discovering the covalent SARS-CoV-2 3CLpro inhibitors from herbal medicines. To decipher the key anti-SARS-CoV-2 3CLpro constituents in Ginkgo biloba extract 50 (GBE50) and to study their anti-SARS-CoV-2 3CLpro mechanisms. Methods : SARS-CoV-2 3CLpro inhibition assay including time-dependent inhibition assays and inactivation kinetic analyses were conducted using a fluorescence-based biochemical assay. The constituents in GBE50 were analyzed by UHPLC-Q-Exactive Orbitrap HRMS. The peptides modified by herbal constituents were characterized by using nanoLC-MS/MS. Results : Following testing the anti-SARS-CoV-2 3CLpro effects of 104 herbal medicines, it was found that Ginkgo biloba extract 50 (GBE50) potently inhibited SARS-CoV-2 3CLpro in dose- and time-dependent manners. A total of 38 constituents were identified from GBE50 by UHPLC-Q-Exactive Orbitrap HRMS, while 26 peptides modified by 18 constituents were identified by chemoproteomic profiling. The anti-SARS-CoV-2 3CLpro effects of 18 identified covalent inhibitors were then validated by performing time-dependent inhibition assays. The results clearly demonstrated that most tested constituents showed time-dependent inhibition on SARS-CoV-2 3CLpro, while gallocatechin and sciadopitysin displayed the most potent anti-SARS-CoV-2 3CLpro effects. Conclusion : Collectively, GBE50 and some constituents in this herbal product could strongly inhibit SARS-CoV-2 3CLpro in dose- and time-dependent manner. Gallocatechin and sciadopitysin were identified as potent SARS-CoV-2 3CLpro inhibitors, which offers promising lead compounds for the development of novel anti-SARS-CoV-2 drugs. Graphical abstract Image, graphical abstract

Ginkgolic acids inhibit SARS-CoV-2 and its variants by blocking the spike protein/ACE2 interplay.

Targeting the interaction between the spike protein receptor binding domain (S-RBD) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and angiotensin-converting enzyme 2 (ACE2) is a potential therapeutic strategy for treating coronavirus disease 2019 (COVID-19). However, we still lack small-molecule drug candidates for this target due to the missing knowledge in the hot spots for the protein-protein interaction. Here, we used NanoBiT technology to identify three Ginkgolic acids from an in-house traditional Chinese medicine (TCM) library, and they interfere with the S-RBD/ACE2 interplay. Our pseudovirus assay showed that one of the compounds, Ginkgolic acid C17:1 (GA171), significantly inhibits the entry of original SARS-CoV-2 and its variants into the ACE2-overexpressed HEK293T cells. We investigated and proposed the binding sites of GA171 on S-RBD by combining molecular docking and molecular dynamics simulations. Site-directed mutagenesis and surface plasmon resonance revealed that GA171 specifically binds to the pocket near R403 and Y505, critical residues of S-RBD for S-RBD interacting with ACE2. Thus, we provide structural insights into developing new small-molecule inhibitors and vaccines against the proposed S-RBD binding site.

Exploring pharmacological active ingredients of traditional Chinese medicine by pharmacotranscriptomic map in ITCM.

With the emergence of high-throughput technologies, computational screening based on gene expression profiles has become one of the most effective methods for drug discovery. More importantly, profile-based approaches remarkably enhance novel drug-disease pair discovery without relying on drug- or disease-specific prior knowledge, which has been widely used in modern medicine. However, profile-based systematic screening of active ingredients of traditional Chinese medicine (TCM) has been scarcely performed due to inadequate pharmacotranscriptomic data. Here, we develop the largest-to-date online TCM active ingredients-based pharmacotranscriptomic platform integrated traditional Chinese medicine (ITCM) for the effective screening of active ingredients. First, we performed unified high-throughput experiments and constructed the largest data repository of 496 representative active ingredients, which was five times larger than the previous one built by our team. The transcriptome-based multi-scale analysis was also performed to elucidate their mechanism. Then, we developed six state-of-art signature search methods to screen active ingredients and determine the optimal signature size for all methods. Moreover, we integrated them into a screening strategy, TCM-Query, to identify the potential active ingredients for the special disease. In addition, we also comprehensively collected the TCM-related resource by literature mining. Finally, we applied ITCM to an active ingredient bavachinin, and two diseases, including prostate cancer and COVID-19, to demonstrate the power of drug discovery. ITCM was aimed to comprehensively explore the active ingredients of TCM and boost studies of pharmacological action and drug discovery. ITCM is available at http://itcm.biotcm.net.

Discovery and mechanism of action of Thonzonium bromide from an FDA-approved drug library with potent and broad-spectrum inhibitory activity against main proteases of human coronaviruses.

Although the effective drugs or vaccines have been developed to prevent the spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), their efficacy may be limited for the viral evolution and immune escape. Thus, it is urgently needed to develop the novel broad-spectrum antiviral agents to control the coronavirus disease 2019 (COVID-19) global pandemic. The 3C-like protease (3CLpro) is a highly conserved cysteine proteinase that plays a pivotal role in processing the viral polyprotein to create non-structural proteins (nsps) for replication and transcription of SARS-CoV-2, making it an attractive antiviral target for developing broad-spectrum antiviral agents against SARS-CoV-2. In this study, we identified Thonzonium bromide as an inhibitor of SARS-CoV-2 3CLpro with an IC50 value of 2.04 ± 0.25 µM by fluorescence resonance energy transfer (FRET)-based enzymatic inhibition assay from the FDA-approved drug library. Next, we determined the inhibitory activity of Thonzonium bromide analogues against SARS-CoV-2 3CLpro and analyzed their structure-activity relationship (SAR). Interestingly, Thonzonium bromide showed better inhibitory activity than other analogues. Further fluorescence quenching assay, enzyme kinetics analysis, circular dichroism (CD) analysis and molecular docking studies showed that Thonzonium bromide inhibited SARS-CoV-2 3CLpro activity by firmly occupying the catalytic site and inducing conformational changes of the protease. In addition, Thonzonium bromide didn't exhibit inhibitory activity on human chymotrypsin C (CTRC) and Dipeptidyl peptidase IV (DPP-IV), indicating that it had a certain selectivity. Finally, we measured the inhibitory activities of Thonzonium bromide against 3CLpro of SARS-CoV, MERS-CoV and HCoV-229E and found that it had the broad-spectrum inhibitory activity against the proteases of human coronaviruses. These results provide the possible mechanism of action of Thonzonium bromide, highlighting its potential efficacy against multiple human coronaviruses.

Integrated microbiome and metabolome analysis reveals the potential therapeutic mechanism of Qing-Fei-Pai-Du decoction in mice with coronavirus-induced pneumonia.

Current studies have shown that gut microbiota may be closely related to the severity of coronavirus disease 2019 (COVID-19) by regulating the host immune response. Qing-Fei-Pai-Du decoction (QFPDD) is the recommended drug for clinical treatment of patients with COVID-19 in China, but whether it exerts a therapeutic effect by modulating the immune response through gut microbiota remains unclear. In this study, we evaluated the therapeutic effects of QFPDD in pneumonia model mice and performed 16S rRNA sequencing and serum and lung tissue metabolomic analysis to explore the underlying mechanisms during the treatment. Then, Spearman correlation analysis was performed on gut microbiome, serum metabolome, and immune-inflammation-related indicators. Our results suggest that QFPDD can restore the richness and diversity of gut microbiota, and multiple gut microbiota (including Alistipes, Odoribacter, Staphylococcus, Lachnospiraceae_NK4A136_group Enterorhabdus, and unclassified_f_Lachnospiraceae) are significantly associated with immune-inflammation-related indicators. In addition, various types of lipid metabolism changes were observed in serum and lung tissue metabolome, especially glycerophospholipids and fatty acids. A total of 27 differential metabolites (DMs) were significantly correlated with immune-inflammation-related indicators, including 9 glycerophospholipids, 7 fatty acids, 3 linoleic acid, 2 eicosanoids, 2 amino acids, 2 bile acids, and 2 others. Interestingly, these DMs showed a good correlation with the gut microbiota affected by QFPDD. The above results suggest that QFPDD can improve the immune function and reduce inflammation in pneumonia model mice by remodeling gut microbiota and host metabolism.

Effectiveness of COVID-19 vaccines against SARS-CoV-2 variants of concern in real-world: a literature review and meta-analysis.

Knowing vaccine effectiveness (VE) against variants of concern (VOCs) in the real-world setting is essential for public health decision-making. A systematic landscape of the VE against a series of clinical outcomes caused by the VOCs in the real-world setting is needed. We systematically searched for studies that evaluated VE against VOCs in the real-world setting and collected individual data. We identified 113 studies meeting the eligibility criteria. We found full vaccination provided strong protection against each clinical outcome with summary VE ranging from 86.8% to 96.0% Alpha, moderate protection against infection caused by Beta, Gamma and Delta with summary VE ranging from 70.9% to 72.8%, strong protection against severe disease caused by Delta with summary VE ranging from 84.9% to 90.3%, limited protection with summary VE of 23.5% (95% CI, 17.0-29.5) against infection and moderate protection with summary VE ranging from 56.5% to 82.4% against severe diseases caused by Omicron. Booster vaccination can provide a substantial improvement in protection against Delta and Omicron, but not as much as the Delta. The meta-regression analysis showed that the VE against the Omicron wanned over time, and the VE against hospitalization declined relatively slowly, compared to against infection. Those findings supported the need for public health measures, increasing booster vaccination coverage in response to current and new infectious waves driven by variants and developing broadly protective vaccines to confront virus evolution.

Antifibrotic Mechanism of Piceatannol in Bleomycin-Induced Pulmonary Fibrosis in Mice.

Background: Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial lung disease characterized by myofibroblast accumulation and extracellular matrix deposition, which lead to irreversible damage of the lung's architecture and the formation of fibrotic lesions. IPF is also a sequela in serious patients with the coronavirus disease 2019 (COVID-19). The molecular mechanisms under pulmonary fibrosis remain unclear, and there is no satisfactory treatment currently available. Piceatannol (PIC) is a naturally occurring resveratrol analog found in a variety of dietary sources such as grapes, passion fruit, and white tea. It has been reported to inhibit liver fibroblast growth and exhibited various antitumor activities, although its role in pulmonary fibrosis has not been established yet. In the present study, we evaluated the anti-fibrotic role of PIC in bleomycin (BLM)-induced pulmonary fibrosis in mice. Methods: Mice with BLM-induced pulmonary fibrosis were treated with PIC, and fibrotic changes were measured by hematoxylin-eosin (H&E) staining and hydroxyproline assay. Luciferase assay, Western blot assay, histological analysis, and immunofluorescence staining were used to evaluate the effect of PIC on fibroblast activation and autophagy in mouse embryonic fibroblast cells (NIH-3T3) and human lung fibroblast cells (HFL1). The anti-fibrotic mechanisms of PIC were either confirmed in vivo. Results: Our results showed that PIC significantly alleviated the bleomycin-induced collagen deposition and myofibroblast accumulation. In vitro and in vivo studies indicated that PIC plays a role in activating autophagy in the process of anti-fibroblast activation. Further mechanism studies demonstrated that PIC can promote autophagy via inhibiting the TGF-ß1-Smad3/ERK/P38 signaling pathway, which leads to a decreased number of activated myofibroblasts. Conclusion: Our study demonstrated for the first time that PIC possesses the protective effects against bleomycin-induced pulmonary fibrosis due to the direct pulmonary protective effects which enhance the effect of autophagy in vitro and in vivo and finally leads to the decreased number of activated myofibroblasts. PIC may serve as a candidate compound for pulmonary fibrosis therapy and attenuates the sequelae of SARS-COV-2 pulmonary fibrosis.

Integrated hepatic single-cell RNA sequencing and untargeted metabolomics reveals the immune and metabolic modulation of Qing-Fei-Pai-Du decoction in mice with coronavirus-induced pneumonia.

BACKGROUND: Although Qing-Fei-Pai-Du decoction (QFPDD) is extensively used clinically to treat COVID-19 patients, the mechanism by which it modulates the immunological and metabolic functions of liver tissue remains unknown. PURPOSE: The purpose of this study is to investigate the mechanism of action of QFPDD in the treatment of mice with coronavirus-induced pneumonia by combining integrated hepatic single-cell RNA sequencing and untargeted metabolomics. METHODS: We developed a human coronavirus pneumonia model in BALB/c mice by infecting them with human coronavirus HCoV-229E with stimulating them with cold-damp environment. We initially assessed the status of inflammation and immunity in model mice treated with or without QFPDD by detecting peripheral blood lymphocytes and inflammatory cytokines. Then, single-cell RNA sequencing and untargeted metabolomics were performed on mouse liver tissue. RESULTS: HCoV-229E infection in combination with exposure to a cold-damp environment significantly decreased the percentage of peripheral blood lymphocytes (CD4+ and CD8+ T cells, B cells) in mice, which was enhanced by QFPDD therapy. Meanwhile, the levels of inflammatory cytokines such as IL-6, TNF-α, and IFN-γ were significantly increased in mouse models but significantly decreased by QFPDD treatment. Single-cell RNA sequencing analysis showed that QFPDD could attenuate disease-associated alterations in gene expression, core transcriptional regulatory networks, and cell-type composition. Computational predictions indicated that QFPDD rectified the observed aberrant patterns of cell-cell communication. Additionally, the metabolic profiles of liver tissue in the Model group were distinct from mice in the Control group, and QFPDD significantly regulated hepatic purine metabolism. CONCLUSION: To the best of our knowledge, this study is the first to integrate hepatic single-cell RNA sequencing and untargeted metabolomics into a TCM formula and these valuable findings indicate that QFPDD can improve immune function and reduce liver injury and inflammation.

Stapled Peptides Targeting SARS-CoV-2 Spike Protein HR1 Inhibit the Fusion of Virus to Its Cell Receptor.

The pandemic of acute respiratory disease in 2019 caused by highly pathogenic and infectious SARS-CoV-2 has seriously endangered human public safety. The 6-HB (HR1-HR2 complex) formation occurring in the process of spike protein-mediated membrane fusion could serve as a conserved and potential target for the design of fusion inhibitors. Based on the HR2 domain of 6-HB, we designed and synthesized 32 stapled peptides using an all-hydrocarbon peptide stapling strategy. Owing to the improved proteolytic stability and higher helical contents, the optimized stapled peptides termed SCH2-1-20 and SCH2-1-27 showed better inhibitory activities against pseudo and authentic SARS-CoV-2 compared to the linear counterpart. Of note, SCH2-1-20 and SCH2-1-27 were proved to interfere with S protein-mediated membrane fusion. Structural modeling indicated similar binding modes between SCH2-1-20 and the linear peptide. These optimized stapled peptides could serve as potent fusion inhibitors in treating and preventing SARS-CoV-2, and the corresponding SAR could facilitate further optimization.

Real-world effectiveness of COVID-19 vaccines: a literature review and meta-analysis.

OBJECTIVE: To estimate the coronavirus disease 2019 (COVID-19) vaccine effectiveness (VE) against concerned outcomes in real-world settings. METHODS: Studies reporting COVID-19 VE from August 6, 2020 to October 6, 2021 were included. The summary VE (with 95% confidence intervals (95% CI)) against disease related to COVID-19 was estimated. The results were presented in forest plots. Predefined subgroup analyses and sensitivity analyses were also performed. RESULTS: A total of 51 records were included in this meta-analysis. In fully vaccinated populations, the VE against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, COVID-19-related hospitalization, admission to the intensive care unit, and death was 89.1% (95% CI 85.6-92.6%), 97.2% (95% CI 96.1-98.3%), 97.4% (95% CI 96.0-98.8%), and 99.0% (95% CI 98.5-99.6%), respectively. The VE against infection in the general population aged ≥16 years, the elderly, and healthcare workers was 86.1% (95% CI 77.8-94.4%), 83.8% (95% CI 77.1-90.6%), and 95.3% (95% CI 92.0-98.6%), respectively. For those fully vaccinated against infection, the observed effectiveness of the Pfizer-BioNTech vaccine was 91.2% and of the Moderna vaccine was 98.1%, while the effectiveness of the CoronaVac vaccine was found to be 65.7%. CONCLUSIONS: The COVID-19 vaccines are highly protective against SARS-CoV-2-related diseases in real-world settings.

Qing-Fei-Pai-Du decoction and wogonoside exert anti-inflammatory action through down-regulating USP14 to promote the degradation of activating transcription factor 2.

COVID-19 is often characterized by dysregulated inflammatory and immune responses. It has been shown that the Traditional Chinese Medicine formulation Qing-Fei-Pai-Du decoction (QFPDD) is effective in the treatment of the disease, especially for patients in the early stage. Our network pharmacology analyses indicated that many inflammation and immune-related molecules were the targets of the active components of QFPDD, which propelled us to examine the effects of the decoction on inflammation. We found in the present study that QFPDD effectively alleviated dextran sulfate sodium-induced intestinal inflammation in mice. It inhibited the production of pro-inflammatory cytokines IL-6 and TNFα, and promoted the expression of anti-inflammatory cytokine IL-10 by macrophagic cells. Further investigations found that QFPDD and one of its active components wogonoside markedly reduced LPS-stimulated phosphorylation of transcription factor ATF2, an important regulator of multiple cytokines expression. Our data revealed that both QFPDD and wogonoside decreased the half-life of ATF2 and promoted its proteasomal degradation. Of note, QFPDD and wogonoside down-regulated deubiquitinating enzyme USP14 along with inducing ATF2 degradation. Inhibition of USP14 with the small molecular inhibitor IU1 also led to the decrease of ATF2 in the cells, indicating that QFPDD and wogonoside may act through regulating USP14 to promote ATF2 degradation. To further assess the importance of ubiquitination in regulating ATF2, we generated mice that were intestinal-specific KLHL5 deficiency, a CUL3-interacting protein participating in substrate recognition of E3s. In these mice, QFPDD mitigated inflammatory reaction in the spleen, but not intestinal inflammation, suggesting CUL3-KLHL5 may function as an E3 for ATF2 degradation.

Inhibition of drug-metabolizing enzymes by Jingyin granules: implications of herb-drug interactions in antiviral therapy.

Jingyin granules, a marketed antiviral herbal medicine, have been recommended for treating H1N1 influenza A virus infection and Coronavirus disease 2019 (COVID-19) in China. To fight viral diseases in a more efficient way, Jingyin granules are frequently co-administered in clinical settings with a variety of therapeutic agents, including antiviral drugs, anti-inflammatory drugs, and other Western medicines. However, it is unclear whether Jingyin granules modulate the pharmacokinetics of Western drugs or trigger clinically significant herb-drug interactions. This study aims to assess the inhibitory potency of the herbal extract of Jingyin granules (HEJG) against human drug-metabolizing enzymes and to clarify whether HEJG can modulate the pharmacokinetic profiles of Western drug(s) in vivo. The results clearly demonstrated that HEJG dose-dependently inhibited human CES1A, CES2A, CYPs1A, 2A6, 2C8, 2C9, 2D6, and 2E1; this herbal medicine also time- and NADPH-dependently inhibited human CYP2C19 and CYP3A. In vivo tests showed that HEJG significantly increased the plasma exposure of lopinavir (a CYP3A-substrate drug) by 2.43-fold and strongly prolonged its half-life by 1.91-fold when HEJG (3 g/kg) was co-administered with lopinavir to rats. Further investigation revealed licochalcone A, licochalcone B, licochalcone C and echinatin in Radix Glycyrrhizae, as well as quercetin and kaempferol in Folium Llicis Purpureae, to be time-dependent CYP3A inhibitors. Collectively, our findings reveal that HEJG modulates the pharmacokinetics of CYP substrate-drug(s) by inactivating CYP3A, providing key information for both clinicians and patients to use herb-drug combinations for antiviral therapy in a scientific and reasonable way.

Comprehensive profiling and characterization of the absorbed components and metabolites in mice serum and tissues following oral administration of Qing-Fei-Pai-Du decoction by UHPLC-Q-Exactive-Orbitrap HRMS.

Qing-Fei-Pai-Du decoction (QFPDD) is a Chinese medicine compound formula recommended for combating corona virus disease 2019 (COVID-19) by National Health Commission of the People's Republic of China. The latest clinical study showed that early treatment with QFPDD was associated with favorable outcomes for patient recovery, viral shedding, hospital stay, and course of the disease. However, the effective constituents of QFPDD remain unclear. In this study, an UHPLC-Q-Orbitrap HRMS based method was developed to identify the chemical constituents in QFPDD and the absorbed prototypes as well as the metabolites in mice serum and tissues following oral administration of QFPDD. A total of 405 chemicals, including 40 kinds of alkaloids, 162 kinds of flavonoids, 44 kinds of organic acids, 71 kinds of triterpene saponins and 88 kinds of other compounds in the water extract of QFPDD were tentatively identified via comparison with the retention times and MS/MS spectra of the standards or refereed by literature. With the help of the standards and in vitro metabolites, 195 chemical components (including 104 prototypes and 91 metabolites) were identified in mice serum after oral administration of QFPDD. In addition, 165, 177, 112, 120, 44, 53 constituents were identified in the lung, liver, heart, kidney, brain, and spleen of QFPDD-treated mice, respectively. These findings provided key information and guidance for further investigation on the pharmacologically active substances and clinical applications of QFPDD.

Inhibition of drug-metabolizing enzymes by Qingfei Paidu decoction: Implication of herb-drug interactions in COVID-19 pharmacotherapy.

Corona Virus Disease 2019 (COVID-19) has spread all over the world and brings significantly negative effects on human health. To fight against COVID-19 in a more efficient way, drug-drug or drug-herb combinations are frequently used in clinical settings. The concomitant use of multiple medications may trigger clinically relevant drug/herb-drug interactions. This study aims to assay the inhibitory potentials of Qingfei Paidu decoction (QPD, a Chinese medicine compound formula recommended for combating COVID-19 in China) against human drug-metabolizing enzymes and to assess the pharmacokinetic interactions in vivo. The results demonstrated that QPD dose-dependently inhibited CYPs1A, 2A6, 2C8, 2C9, 2C19, 2D6 and 2E1 but inhibited CYP3A in a time- and NADPH-dependent manner. In vivo test showed that QPD prolonged the half-life of lopinavir (a CYP3A substrate-drug) by 1.40-fold and increased the AUC of lopinavir by 2.04-fold, when QPD (6 g/kg) was co-administrated with lopinavir (160 mg/kg) to rats. Further investigation revealed that Fructus Aurantii Immaturus (Zhishi) in QPD caused significant loss of CYP3A activity in NADPH-generating system. Collectively, our findings revealed that QPD potently inactivated CYP3A and significantly modulated the pharmacokinetics of CYP3A substrate-drugs, which would be very helpful for the patients and clinicians to avoid potential drug-interaction risks in COVID-19 treatment.

Systems pharmacological study illustrates the immune regulation, anti-infection, anti-inflammation, and multi-organ protection mechanism of Qing-Fei-Pai-Du decoction in the treatment of COVID-19.

BACKGROUND: The traditional Chinese medicine (TCM) formula Qing-Fei-Pai-Du decoction (QFPDD) was the most widely used prescription in China's campaign to contain COVID-19, which has exhibited positive effects. However, the underlying mode of action is largely unknown. PURPOSE: A systems pharmacology strategy was proposed to investigate the mechanisms of QFPDD against COVID-19 from molecule, pathway and network levels. STUDY DESIGN AND METHODS: The systems pharmacological approach consisted of text mining, target prediction, data integration, network study, bioinformatics analysis, molecular docking, and pharmacological validation. Especially, we proposed a scoring method to measure the confidence of targets identified by prediction and text mining, while a novel scheme was used to identify important targets from 4 aspects. RESULTS: 623 high-confidence targets of QFPDD's 12 active compounds were identified, 88 of which were overlapped with genes affected by SARS-CoV-2 infection. These targets were found to be involved in biological processes related with the development of COVID-19, such as pattern recognition receptor signaling, interleukin signaling, cell growth and death, hemostasis, and injuries of the nervous, sensory, circulatory, and digestive systems. Comprehensive network and pathway analysis were used to identify 55 important targets, which regulated 5 functional modules corresponding to QFPDD's effects in immune regulation, anti-infection, anti-inflammation, and multi-organ protection, respectively. Four compounds (baicalin, glycyrrhizic acid, hesperidin, and hyperoside) and 7 targets (AKT1, TNF-α, IL6, PTGS2, HMOX1, IL10, and TP53) were key molecules related to QFPDD's effects. Molecular docking verified that QFPDD's compounds may bind to 6 host proteins that interact with SARS-CoV-2 proteins, further supported the anti-virus effect of QFPDD. At last, in intro experiments validated QFPDD's important effects, including the inhibition of IL6, CCL2, TNF-α, NF-κB, PTGS1/2, CYP1A1, CYP3A4 activity, the up-regulation of IL10 expression, and repressing platelet aggregation. CONCLUSION: This work illustrated that QFPDD could exhibit immune regulation, anti-infection, anti-inflammation, and multi-organ protection. It may strengthen the understanding of QFPDD and facilitate more application of this formula in the campaign to SARS-CoV-2.

[Investigation of modulating effect of Qingfei Paidu Decoction on host metabolism and gut microbiome in rats].

This study is to explore the effect of Qingfei Paidu Decoction(QPD) on the host metabolism and gut microbiome of rats with metabolomics and 16 S rDNA sequencing. Based on 16 S rDNA sequencing of gut microbiome and metabolomics(GC-MS and LC-MS/MS), we systematically studied the serum metabolites profile and gut microbiota composition of rats treated with QPD for continued 5 days by oral gavage. A total of 23 and 43 differential metabolites were identified based on QPD with GC-MS and LC-MS/MS, respectively. The involved metabolic pathways of these differential metabolites included glycerophospholipid metabolism, linoleic acid metabolism, TCA cycle and pyruvate metabolism. Meanwhile, we found that QPD significantly regulated the composition of gut microbiota in rats, such as enriched Romboutsia, Turicibacter, and Clostridium_sensu_stricto_1, and decreased norank_f_Lachnospiraceae. Our current study indicated that short-term intervention of QPD could significantly regulate the host metabolism and gut microbiota composition of rats dose-dependently, suggesting that the clinical efficacy of QPD may be related with the regulation on host metabolism and gut microbiome.

Comprehensive identification and isolation policies have effectively suppressed the spread of COVID-19.

The outbreak of COVID-19 has caused severe life and economic damage worldwide. Since the absence of medical resources or targeted therapeutics, systemic containment policies have been prioritized but some critics query what extent can they mitigate this pandemic. We construct a fine-grained transmission dynamics model to forecast the crucial information of public concern, therein using dynamical coefficients to quantify the impact of the implement schedule and intensity of the containment policies on the spread of epidemic. Statistical evidences show the comprehensive identification and quarantine policies eminently contributed to reduce casualties during the phase of a dramatic increase in diagnosed cases in Wuhan and postponing or weakening such policies would undoubtedly exacerbate the epidemic. Hence we suggest that governments should swiftly execute the forceful public health interventions in the initial stage until the pandemic is blocked.