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1.
J Med Chem ; 64(23): 17486-17495, 2021 12 09.
Article in English | MEDLINE | ID: covidwho-1531976

ABSTRACT

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.


Subject(s)
Spike Glycoprotein, Coronavirus , Membrane Fusion , Pandemics , Protein Binding
2.
Acta Pharmacol Sin ; 43(4): 1072-1081, 2022 Apr.
Article in English | MEDLINE | ID: covidwho-1285959

ABSTRACT

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.


Subject(s)
COVID-19 , Influenza A Virus, H1N1 Subtype , Animals , Antiviral Agents/pharmacology , COVID-19/drug therapy , Cytochrome P-450 CYP3A Inhibitors , Herb-Drug Interactions , Humans , Microsomes, Liver , Rats
3.
Chin J Nat Med ; 19(4): 305-320, 2021 Apr.
Article in English | MEDLINE | ID: covidwho-1193536

ABSTRACT

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.


Subject(s)
Drugs, Chinese Herbal/chemistry , Drugs, Chinese Herbal/pharmacokinetics , Administration, Oral , Alkaloids/analysis , Animals , COVID-19 , Chromatography, High Pressure Liquid , Flavonoids/analysis , Mice , SARS-CoV-2 , Saponins/analysis , Triterpenes/analysis
4.
Food Chem Toxicol ; 149: 111998, 2021 Mar.
Article in English | MEDLINE | ID: covidwho-1139497

ABSTRACT

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.


Subject(s)
COVID-19/drug therapy , Cytochrome P-450 CYP3A/metabolism , Drugs, Chinese Herbal/pharmacology , Herb-Drug Interactions , Animals , Area Under Curve , China , Drugs, Chinese Herbal/therapeutic use , Lopinavir/pharmacokinetics , Male , Microsomes, Liver , NADP/metabolism , Phytotherapy , Rats, Sprague-Dawley , SARS-CoV-2
5.
Zhongguo Zhong Yao Za Zhi ; 45(15): 3726-3739, 2020 Aug.
Article in Chinese | MEDLINE | ID: covidwho-745644

ABSTRACT

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.


Subject(s)
Drugs, Chinese Herbal/pharmacology , Gastrointestinal Microbiome/drug effects , Animals , Bacteria/classification , Chromatography, Liquid , Metabolomics , Rats , Tandem Mass Spectrometry
6.
Chin. Trad. Herbal Drugs ; 4(51): 829-835, 20200228.
Article in Chinese | WHO COVID, ELSEVIER | ID: covidwho-45770

ABSTRACT

Objective: To collect main ingredients and targets of Qing-Fei-Pai-Du-Tang (QFPDT), and to investigate the relationship between the targets and coronavirus disease 2019 (COVID-19) and the multi-component, multi-target mechanism of QFPDT for the treatment of COVID-19. Methods: The meridian tropisms, compounds and targets of each herb in QFPDT were collected from ETCM, TCMID and NPASS databases. Cytoscape software was used to construct and analyze networks. DAVID and STRING were applied for functional enrichment analysis of targets. Results: The top meridian tropism of herbs in QFPDT was lung meridian. Among QFPDT’s 790 putative targets, 232 targets were co-expressed with ACE2, the receptor of novel coronavirus (SARS-CoV-2). The targets included seven densely interacting ribosomal proteins. Important targets were enriched on two classes of disease pathways, i.e., virus infection and lung injury. In addition, many targets interacted with six proteins of HIV virus. Important targets regulated a series of pathways belong to translation, endocrine system, immune system, nervous system and signal transduction. Conclusion: The main targeting organ of QFPDT is the lung and the second is the spleen. By regulating a series of proteins co-expressed with ACE2 and a series of signaling pathways closely related to the occurrence and development of diseases, it plays a role in balancing immunity and eliminating inflammation. It may act as an antiviral agent by targeting ribosomal proteins that are necessary for viral replication to inhibit viral mRNA translation and inhibiting a group of proteins that interact with viral proteins.

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