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1.
Nan Fang Yi Ke Da Xue Xue Bao ; 42(6): 955-956, 2022 Jun 20.
Article in Chinese | MEDLINE | ID: covidwho-1924684

ABSTRACT

As a member of the dibenzyl isoquinoline alkaloid family, cepharathine is an alkaloid from the traditional Chinese medicine cepharathine, which is mainly used for treatment of leukopenia and other diseases. Recent studies of the inhibitory effect of cepharathine against SARS-CoV-2 have attracted widespread attention and aroused heated discussion. As the original discoverer of the anti-SARS-CoV-2 activity of cepharanthine, here we briefly summarize the discovery of cepharanthine and review important progress in relevant studies concerning the discovery and validation of anti-SARS-CoV-2 activity of cepharathine, its antiviral mechanisms and clinical trials of its applications in COVID-19 therapy.


Subject(s)
Benzylisoquinolines , COVID-19 , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Benzylisoquinolines/pharmacology , Benzylisoquinolines/therapeutic use , Humans , SARS-CoV-2
2.
Viruses ; 14(6)2022 06 06.
Article in English | MEDLINE | ID: covidwho-1911617

ABSTRACT

Porcine epidemic diarrhea virus (PEDV) belongs to the genus Alphacoronavirus of the family Coronaviridae that causes severe diarrhea and high mortality in neonatal suckling piglets. Currently, there is no effective medication against this pathogen. Cepharanthine (CEP), tetrandrine (TET), and fangchinoline (FAN) are natural bis-benzylisoquinoline alkaloids with anti-inflammatory, antitumor, and antiviral properties. Here, we first found that CEP, TET, and FAN had anti-PEDV activity with IC50 values of 2.53, 3.50, and 6.69 µM, respectively. The compounds could block all the processes of viral cycles, but early application of the compounds before or during virus infection was advantageous over application at a late stage of virus replication. FAN performed inhibitory function more efficiently through interfering with the virus entry and attachment processes or through attenuating the virus directly. CEP had a more notable effect on virus entry. With the highest SI index of 11.8 among the three compounds, CEP was chosen to carry out animal experiments. CEP in a safe dosage of 11.1 mg/kg of body weight could reduce viral load and pathological change of piglet intestinal tracts caused by PEDV field strain challenge, indicating that CEP efficiently inhibited PEDV infection in vivo. All of these results demonstrated that the compounds of bis-benzylisoquinoline alkaloids could inhibit PEDV proliferation efficiently and had the potential of being developed for PED prevention and treatment.


Subject(s)
Benzylisoquinolines , Coronavirus Infections , Porcine epidemic diarrhea virus , Swine Diseases , Animals , Benzylisoquinolines/pharmacology , Coronavirus Infections/drug therapy , Coronavirus Infections/pathology , Coronavirus Infections/veterinary , Diarrhea , Swine , Swine Diseases/pathology
3.
Molecules ; 27(9)2022 Apr 24.
Article in English | MEDLINE | ID: covidwho-1810048

ABSTRACT

Cepharanthine (CEP) has excellent anti-SARS-CoV-2 properties, indicating its favorable potential for COVID-19 treatment. However, its application is challenged by its poor dissolubility and oral bioavailability. The present study aimed to improve the bioavailability of CEP by optimizing its solubility and through a pulmonary delivery method, which improved its bioavailability by five times when compared to that through the oral delivery method (68.07% vs. 13.15%). An ultra-performance liquid chromatography tandem-mass spectrometry (UPLC-MS/MS) method for quantification of CEP in rat plasma was developed and validated to support the bioavailability and pharmacokinetic studies. In addition, pulmonary fibrosis was recognized as a sequela of COVID-19 infection, warranting further evaluation of the therapeutic potential of CEP on a rat lung fibrosis model. The antifibrotic effect was assessed by analysis of lung index and histopathological examination, detection of transforming growth factor (TGF)-ß1, interleukin-6 (IL-6), α-smooth muscle actin (α-SMA), and hydroxyproline level in serum or lung tissues. Our data demonstrated that CEP could significantly alleviate bleomycin (BLM)-induced collagen accumulation and inflammation, thereby exerting protective effects against pulmonary fibrosis. Our results provide evidence supporting the hypothesis that pulmonary delivery CEP may be a promising therapy for pulmonary fibrosis associated with COVID-19 infection.


Subject(s)
COVID-19 , Pulmonary Fibrosis , Animals , Benzylisoquinolines , Biological Availability , Bleomycin/pharmacology , COVID-19/complications , COVID-19/drug therapy , Chromatography, Liquid , Humans , Lung , Pulmonary Fibrosis/chemically induced , Pulmonary Fibrosis/etiology , Rats , Tandem Mass Spectrometry , Transforming Growth Factor beta1/metabolism
4.
PLoS Negl Trop Dis ; 16(4): e0010363, 2022 04.
Article in English | MEDLINE | ID: covidwho-1808522

ABSTRACT

COVID-19 caused by SARS-CoV-2 has posed a significant threat to global public health since its outbreak in late 2019. Although there are a few drugs approved for clinical treatment to combat SARS-CoV-2 infection currently, the severity of the ongoing global pandemic still urges the efforts to discover new antiviral compounds. As the viral spike (S) protein plays a key role in mediating virus entry, it becomes a potential target for the design of antiviral drugs against COVID-19. Here, we tested the antiviral activity of berbamine hydrochloride, a bis-benzylisoquinoline alkaloid, against SARS-CoV-2 infection. We found that berbamine hydrochloride could efficiently inhibit SARS-CoV-2 infection in different cell lines. Further experiments showed berbamine hydrochloride inhibits SARS-CoV-2 infection by targeting the viral entry into host cells. Moreover, berbamine hydrochloride and other bis-benzylisoquinoline alkaloids could potently inhibit S-mediated cell-cell fusion. Furthermore, molecular docking results implied that the berbamine hydrochloride could bind to the post fusion core of SARS-CoV-2 S2 subunit. Therefore, berbamine hydrochloride may represent a potential efficient antiviral agent against SARS-CoV-2 infection.


Subject(s)
Benzylisoquinolines , COVID-19 , Antiviral Agents/pharmacology , Benzylisoquinolines/pharmacology , COVID-19/drug therapy , Humans , Membrane Fusion , Molecular Docking Simulation , SARS-CoV-2 , Spike Glycoprotein, Coronavirus , Virus Internalization
5.
FEBS Open Bio ; 12(1): 285-294, 2022 01.
Article in English | MEDLINE | ID: covidwho-1540045

ABSTRACT

Cepharanthine (CEP) is a natural biscoclaurine alkaloid of plant origin and was recently demonstrated to have anti-severe acute respiratory syndrome coronavirus 2 (anti-SARS-CoV-2) activity. In this study, we evaluated whether natural analogues of CEP may act as potential anti-coronavirus disease 2019 drugs. A total of 24 compounds resembling CEP were extracted from the KNApSAcK database, and their binding affinities to target proteins, including the spike protein and main protease of SARS-CoV-2, NPC1 and TPC2 in humans, were predicted via molecular docking simulations. Selected analogues were further evaluated by a cell-based SARS-CoV-2 infection assay. In addition, the efficacies of CEP and its analogue tetrandrine were assessed. A comparison of the docking conformations of these compounds suggested that the diphenyl ester moiety of the molecules was a putative pharmacophore of the CEP analogues.


Subject(s)
Antiviral Agents/pharmacology , Benzylisoquinolines/pharmacology , COVID-19/prevention & control , Plant Preparations/pharmacology , SARS-CoV-2/drug effects , Animals , Antiviral Agents/chemistry , Antiviral Agents/metabolism , Benzylisoquinolines/chemistry , Benzylisoquinolines/metabolism , COVID-19/virology , Chlorocebus aethiops , Coronavirus M Proteins/antagonists & inhibitors , Coronavirus M Proteins/chemistry , Coronavirus M Proteins/metabolism , Drug Evaluation, Preclinical/methods , Humans , Molecular Docking Simulation , Molecular Dynamics Simulation , Plant Preparations/chemistry , Plant Preparations/metabolism , Protein Binding , Protein Conformation , SARS-CoV-2/metabolism , SARS-CoV-2/physiology , Stephania/chemistry , Vero Cells
6.
J Mol Graph Model ; 109: 108028, 2021 12.
Article in English | MEDLINE | ID: covidwho-1458654

ABSTRACT

Owing to the shortage of specific medicines, the global pandemic of COVID-19 caused by SARS-CoV-2 has been the greatest challenge for the science community. Researchers from all over the world developed some drugs which failed to completely suppress the contiguous disease. SARS-CoV-2 main protease (Mpro), an important component in viral pathogenesis, is considered as a prospective drug target to stop SARS-CoV-2 infection. Since identification of phytochemicals with anti-Mpro activity has been carried out to develop the potential drugs against SARS-CoV-2. Therefore, the present study was conducted to screen phytochemicals of Berberis asiatica for anti-SARS-CoV-2 activity. Through text mining, thirty phytochemicals were reported from B. asiatica, of which, three phytochemicals (Berbamine, Oxyacanthine, and Rutin) show high affinity with the SARS-CoV-2 Mpro and exhibited favorable intermolecular interactions with the catalytic residues (His41 and Cys145) and other essential residues. The molecular dynamics simulation showed that Mpro-phytochemical complexes are more stable, less fluctuating, more compact, and moderately extended than the Mpro-X77 (Reference) complex. The number of H-bonds and MMPBSA results also demonstrates that Berbamine, Oxyacanthine, and Rutin are potent Mpro inhibitors having free energy of -20.79, -33.35, and -31.12 kcal mol-1 respectively. The toxicity risk prediction supports all phytochemicals for drug-like and non-toxic nature. From the result, we propose that binding of these phytochemicals could hamper the function of Mpro. This work suggests that selected phytochemicals could be used as novel anti-COVID-19 drug candidates, and might act as novel compounds for in vitro and in vivo study.


Subject(s)
Berberis , COVID-19 , Benzylisoquinolines , Humans , Isoquinolines , Molecular Docking Simulation , Molecular Dynamics Simulation , Protease Inhibitors , Rutin , SARS-CoV-2
7.
J Med Virol ; 93(10): 5825-5832, 2021 10.
Article in English | MEDLINE | ID: covidwho-1432413

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic has focused attention on the need to develop effective therapeutics against the causative pathogen, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and also against other pathogenic coronaviruses. In this study, we report on a kind of bisbenzylisoquinoline alkaloid, neferine, as a pan-coronavirus entry inhibitor. Neferine effectively protected HEK293/hACE2 and HuH7 cell lines from infection by different coronaviruses pseudovirus particles (SARS-CoV-2, SARS-CoV-2 [D614G, N501Y/D614G, 501Y.V1, 501Y.V2, 501Y.V3 variants], SARS-CoV, MERS-CoV) in vitro, with median effect concentration (EC50 ) of 0.13-0.41 µM. Neferine blocked host calcium channels, thus inhibiting Ca2+ -dependent membrane fusion and suppressing virus entry. This study provides experimental data to support the fact that neferine may be a promising lead for pan-coronaviruses therapeutic drug development.


Subject(s)
Antiviral Agents/pharmacology , Benzylisoquinolines/pharmacology , Calcium/metabolism , SARS-CoV-2/drug effects , Virus Internalization/drug effects , COVID-19/virology , Cell Line , Coronavirus/drug effects , Coronavirus/physiology , HEK293 Cells , Humans , Isoquinolines/pharmacology , Phenols/pharmacology , SARS-CoV-2/physiology
10.
Brief Bioinform ; 22(2): 1378-1386, 2021 03 22.
Article in English | MEDLINE | ID: covidwho-1352117

ABSTRACT

Antiviral therapies targeting the pandemic coronavirus disease 2019 (COVID-19) are urgently required. We studied an already-approved botanical drug cepharanthine (CEP) in a cell culture model of GX_P2V, a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-related virus. RNA-sequencing results showed the virus perturbed the expression of multiple genes including those associated with cellular stress responses such as endoplasmic reticulum (ER) stress and heat shock factor 1 (HSF1)-mediated heat shock response, of which heat shock response-related genes and pathways were at the core. CEP was potent to reverse most dysregulated genes and pathways in infected cells including ER stress/unfolded protein response and HSF1-mediated heat shock response. Additionally, single-cell transcriptomes also confirmed that genes of cellular stress responses and autophagy pathways were enriched in several peripheral blood mononuclear cells populations from COVID-19 patients. In summary, this study uncovered the transcriptome of a SARS-CoV-2-related coronavirus infection model and anti-viral activities of CEP, providing evidence for CEP as a promising therapeutic option for SARS-CoV-2 infection.


Subject(s)
Antiviral Agents/pharmacology , Benzylisoquinolines/pharmacology , SARS-CoV-2/drug effects , Transcriptome , Animals , Chlorocebus aethiops , Homeostasis , Humans , Vero Cells
11.
Brief Bioinform ; 22(2): 1378-1386, 2021 03 22.
Article in English | MEDLINE | ID: covidwho-1015212

ABSTRACT

Antiviral therapies targeting the pandemic coronavirus disease 2019 (COVID-19) are urgently required. We studied an already-approved botanical drug cepharanthine (CEP) in a cell culture model of GX_P2V, a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-related virus. RNA-sequencing results showed the virus perturbed the expression of multiple genes including those associated with cellular stress responses such as endoplasmic reticulum (ER) stress and heat shock factor 1 (HSF1)-mediated heat shock response, of which heat shock response-related genes and pathways were at the core. CEP was potent to reverse most dysregulated genes and pathways in infected cells including ER stress/unfolded protein response and HSF1-mediated heat shock response. Additionally, single-cell transcriptomes also confirmed that genes of cellular stress responses and autophagy pathways were enriched in several peripheral blood mononuclear cells populations from COVID-19 patients. In summary, this study uncovered the transcriptome of a SARS-CoV-2-related coronavirus infection model and anti-viral activities of CEP, providing evidence for CEP as a promising therapeutic option for SARS-CoV-2 infection.


Subject(s)
Antiviral Agents/pharmacology , Benzylisoquinolines/pharmacology , SARS-CoV-2/drug effects , Transcriptome , Animals , Chlorocebus aethiops , Homeostasis , Humans , Vero Cells
12.
Pharmacol Res Perspect ; 8(5): e00653, 2020 10.
Article in English | MEDLINE | ID: covidwho-757850

ABSTRACT

More than ten million patients worldwide have been diagnosed with coronavirus disease 19 (COVID-19) to date (WHO situation report, 1st July 2020). There is no vaccine to prevent infection with the causative organism, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), nor a cure. In the struggle to devise potentially useful therapeutics in record time, the repurposing of existing compounds is a key route of action. In this hypothesis paper, we argue that the bisbenzylisoquinoline and calcium channel blocker tetrandrine, originally extracted from the plant Stephania tetrandra and utilized in traditional Chinese medicine, may have potential in the treatment of COVID-19 and should be further investigated. We collate and review evidence for tetrandrine's putative mechanism of action in viral infection, specifically its recently discovered antagonism of the two-pore channel 2 (TPC2). While tetrandrine's particular history of use provides a very limited pharmacological dataset, there is a suggestion from the available evidence that it could be effective at doses used in clinical practice. We suggest that further research to investigate this possibility should be conducted.


Subject(s)
Antiviral Agents/administration & dosage , Benzylisoquinolines/administration & dosage , Betacoronavirus/drug effects , Calcium Channel Blockers/administration & dosage , Calcium Channels/drug effects , Coronavirus Infections/drug therapy , Pneumonia, Viral/drug therapy , Animals , Antiviral Agents/adverse effects , Benzylisoquinolines/adverse effects , Betacoronavirus/pathogenicity , COVID-19 , Calcium Channel Blockers/adverse effects , Calcium Channels/metabolism , Coronavirus Infections/diagnosis , Coronavirus Infections/metabolism , Coronavirus Infections/virology , Drug Interactions , Host-Pathogen Interactions , Humans , Pandemics , Pneumonia, Viral/diagnosis , Pneumonia, Viral/metabolism , Pneumonia, Viral/virology , SARS-CoV-2 , Signal Transduction
13.
Pharmacol Rep ; 72(6): 1509-1516, 2020 Dec.
Article in English | MEDLINE | ID: covidwho-662484

ABSTRACT

Cepharanthine (CEP) is a naturally occurring alkaloid derived from Stephania cepharantha Hayata and demonstrated to have unique anti-inflammatory, antioxidative, immunomodulating, antiparasitic, and antiviral properties. Its therapeutic potential as an antiviral agent has never been more important than in combating COVID-19 caused by severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) virus. Cepharanthine suppresses nuclear factor-kappa B (NF-κB) activation, lipid peroxidation, nitric oxide (NO) production, cytokine production, and expression of cyclooxygenase; all of which are crucial to viral replication and inflammatory response. Against SARS-CoV-2 and homologous viruses, CEP predominantly inhibits viral entry and replication at low doses; and was recently identified as the most potent coronavirus inhibitor among 2406 clinically approved drug repurposing candidates in a preclinical model. This review critically analyzes and consolidates available evidence establishing CEP's potential therapeutic importance as a drug of choice in managing COVID-19 cases.


Subject(s)
Antiviral Agents/therapeutic use , Benzylisoquinolines/therapeutic use , COVID-19/drug therapy , Animals , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/therapeutic use , Antiviral Agents/pharmacology , Benzylisoquinolines/pharmacology , COVID-19/virology , Drug Repositioning , Humans , Inflammation/drug therapy , Inflammation/virology , Japan , SARS-CoV-2/drug effects , SARS-CoV-2/isolation & purification , Virus Replication/drug effects
14.
FASEB J ; 34(6): 7253-7264, 2020 06.
Article in English | MEDLINE | ID: covidwho-175986

ABSTRACT

Drug repurposing is potentially the fastest available option in the race to identify safe and efficacious drugs that can be used to prevent and/or treat COVID-19. By describing the life cycle of the newly emergent coronavirus, SARS-CoV-2, in light of emerging data on the therapeutic efficacy of various repurposed antimicrobials undergoing testing against the virus, we highlight in this review a possible mechanistic convergence between some of these tested compounds. Specifically, we propose that the lysosomotropic effects of hydroxychloroquine and several other drugs undergoing testing may be responsible for their demonstrated in vitro antiviral activities against COVID-19. Moreover, we propose that Niemann-Pick disease type C (NPC), a lysosomal storage disorder, may provide new insights into potential future therapeutic targets for SARS-CoV-2, by highlighting key established features of the disorder that together result in an "unfavorable" host cellular environment that may interfere with viral propagation. Our reasoning evolves from previous biochemical and cell biology findings related to NPC, coupled with the rapidly evolving data on COVID-19. Our overall aim is to suggest that pharmacological interventions targeting lysosomal function in general, and those particularly capable of reversibly inducing transient NPC-like cellular and biochemical phenotypes, constitute plausible mechanisms that could be used to therapeutically target COVID-19.


Subject(s)
Antiviral Agents/pharmacokinetics , Betacoronavirus/physiology , Coronavirus Infections/drug therapy , Drug Repositioning , Endosomes/virology , Hydroxychloroquine/pharmacology , Lysosomes/virology , Niemann-Pick Disease, Type C/pathology , Pneumonia, Viral/drug therapy , ADAM17 Protein/physiology , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/pharmacology , Adenosine Monophosphate/therapeutic use , Alanine/analogs & derivatives , Alanine/pharmacology , Alanine/therapeutic use , Angiotensin-Converting Enzyme 2 , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Benzylisoquinolines/pharmacology , Benzylisoquinolines/therapeutic use , Biological Transport , COVID-19 , Cathepsin L/physiology , Endocytosis , Endosomes/drug effects , Endosomes/physiology , Glycopeptides/pharmacology , Glycopeptides/therapeutic use , Humans , Hydroxychloroquine/pharmacokinetics , Hydroxychloroquine/therapeutic use , Intracellular Signaling Peptides and Proteins/antagonists & inhibitors , Intracellular Signaling Peptides and Proteins/deficiency , Intracellular Signaling Peptides and Proteins/physiology , Lysosomes/drug effects , Lysosomes/metabolism , Membrane Lipids/metabolism , Membrane Microdomains/physiology , Niemann-Pick C1 Protein , Niemann-Pick Disease, Type C/metabolism , Oxysterols/metabolism , Pandemics , Peptidyl-Dipeptidase A/metabolism , Receptors, Virus/metabolism , SARS-CoV-2 , Serine Endopeptidases/physiology , Triazoles/pharmacology , Triazoles/therapeutic use , Virus Internalization/drug effects
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