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1.
Viruses ; 14(2)2022 01 18.
Article in English | MEDLINE | ID: covidwho-1649476

ABSTRACT

Recurrent outbreaks of novel zoonotic coronavirus (CoV) diseases in recent years have highlighted the importance of developing therapeutics with broad-spectrum activity against CoVs. Because all CoVs use -1 programmed ribosomal frameshifting (-1 PRF) to control expression of key viral proteins, the frameshift signal in viral mRNA that stimulates -1 PRF provides a promising potential target for such therapeutics. To test the viability of this strategy, we explored whether small-molecule inhibitors of -1 PRF in SARS-CoV-2 also inhibited -1 PRF in a range of bat CoVs-the most likely source of future zoonoses. Six inhibitors identified in new and previous screens against SARS-CoV-2 were evaluated against the frameshift signals from a panel of representative bat CoVs as well as MERS-CoV. Some drugs had strong activity against subsets of these CoV-derived frameshift signals, while having limited to no effect on -1 PRF caused by frameshift signals from other viruses used as negative controls. Notably, the serine protease inhibitor nafamostat suppressed -1 PRF significantly for multiple CoV-derived frameshift signals. These results suggest it is possible to find small-molecule ligands that inhibit -1 PRF specifically in a broad spectrum of CoVs, establishing frameshift signals as a viable target for developing pan-coronaviral therapeutics.


Subject(s)
Antiviral Agents/pharmacology , Coronavirus/drug effects , Coronavirus/genetics , Frameshift Mutation , Frameshifting, Ribosomal/drug effects , Viral Proteins/antagonists & inhibitors , Animals , Antiviral Agents/therapeutic use , Chiroptera/virology , Coronavirus/classification , Coronavirus Infections/drug therapy , Nucleic Acid Conformation , RNA, Messenger/genetics , SARS-CoV-2/drug effects , SARS-CoV-2/genetics , Viral Proteins/genetics , Virus Replication/drug effects
2.
Science ; 374(6575): 1586-1593, 2021 Dec 24.
Article in English | MEDLINE | ID: covidwho-1666355

ABSTRACT

The worldwide outbreak of COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a global pandemic. Alongside vaccines, antiviral therapeutics are an important part of the healthcare response to countering the ongoing threat presented by COVID-19. Here, we report the discovery and characterization of PF-07321332, an orally bioavailable SARS-CoV-2 main protease inhibitor with in vitro pan-human coronavirus antiviral activity and excellent off-target selectivity and in vivo safety profiles. PF-07321332 has demonstrated oral activity in a mouse-adapted SARS-CoV-2 model and has achieved oral plasma concentrations exceeding the in vitro antiviral cell potency in a phase 1 clinical trial in healthy human participants.


Subject(s)
COVID-19/drug therapy , Lactams/pharmacology , Lactams/therapeutic use , Leucine/pharmacology , Leucine/therapeutic use , Nitriles/pharmacology , Nitriles/therapeutic use , Proline/pharmacology , Proline/therapeutic use , SARS-CoV-2/drug effects , Viral Protease Inhibitors/pharmacology , Viral Protease Inhibitors/therapeutic use , Administration, Oral , Animals , COVID-19/virology , Clinical Trials, Phase I as Topic , Coronavirus/drug effects , Disease Models, Animal , Drug Therapy, Combination , Humans , Lactams/administration & dosage , Lactams/pharmacokinetics , Leucine/administration & dosage , Leucine/pharmacokinetics , Mice , Mice, Inbred BALB C , Microbial Sensitivity Tests , Nitriles/administration & dosage , Nitriles/pharmacokinetics , Proline/administration & dosage , Proline/pharmacokinetics , Randomized Controlled Trials as Topic , Ritonavir/administration & dosage , Ritonavir/therapeutic use , SARS-CoV-2/physiology , Viral Protease Inhibitors/administration & dosage , Viral Protease Inhibitors/pharmacokinetics , Virus Replication/drug effects
3.
Med Sci Monit ; 28: e934102, 2022 Jan 25.
Article in English | MEDLINE | ID: covidwho-1651076

ABSTRACT

BACKGROUND Heat-clearing and detoxifying herbs (HDHs) play an important role in the prevention and treatment of coronavirus infection. However, their mechanism of action needs further study. This study aimed to explore the anti-coronavirus basis and mechanism of HDHs. MATERIAL AND METHODS Database mining was performed on 7 HDHs. Core ingredients and targets were screened according to ADME rules combined with Neighborhood, Co-occurrence, Co-expression, and other algorithms. GO enrichment and KEGG pathway analyses were performed using the R language. Finally, high-throughput molecular docking was used for verification. RESULTS HDHs mainly acts on NOS3, EGFR, IL-6, MAPK8, PTGS2, MAPK14, NFKB1, and CASP3 through quercetin, luteolin, wogonin, indirubin alkaloids, ß-sitosterol, and isolariciresinol. These targets are mainly involved in the regulation of biological processes such as inflammation, activation of MAPK activity, and positive regulation of NF-kappaB transcription factor activity. Pathway analysis further revealed that the pathways regulated by these targets mainly include: signaling pathways related to viral and bacterial infections such as tuberculosis, influenza A, Ras signaling pathways; inflammation-related pathways such as the TLR, TNF, MAPK, and HIF-1 signaling pathways; and immune-related pathways such as NOD receptor signaling pathways. These pathways play a synergistic role in inhibiting lung inflammation and regulating immunity and antiviral activity. CONCLUSIONS HDHs play a role in the treatment of coronavirus infection by regulating the body's immunity, fighting inflammation, and antiviral activities, suggesting a molecular basis and new strategies for the treatment of COVID-19 and a foundation for the screening of new antiviral drugs.


Subject(s)
COVID-19/drug therapy , Coronavirus/drug effects , Drugs, Chinese Herbal/pharmacology , SARS-CoV-2/drug effects , Alkaloids/chemistry , Alkaloids/pharmacology , Caspase 3/drug effects , Caspase 3/genetics , Coronavirus/metabolism , Coronavirus Infections/drug therapy , Cyclooxygenase 2/drug effects , Cyclooxygenase 2/genetics , Databases, Pharmaceutical , Drugs, Chinese Herbal/chemistry , Drugs, Chinese Herbal/therapeutic use , Flavanones/chemistry , Flavanones/pharmacology , Humans , Indoles/chemistry , Indoles/pharmacology , Interleukin-6/genetics , Lignin/chemistry , Lignin/pharmacology , Luteolin/chemistry , Luteolin/pharmacology , Mitogen-Activated Protein Kinase 14/drug effects , Mitogen-Activated Protein Kinase 14/genetics , Mitogen-Activated Protein Kinase 8/drug effects , Mitogen-Activated Protein Kinase 8/genetics , Molecular Docking Simulation , NF-kappa B p50 Subunit/drug effects , NF-kappa B p50 Subunit/genetics , Naphthols/chemistry , Naphthols/pharmacology , Nitric Oxide Synthase Type III/drug effects , Nitric Oxide Synthase Type III/genetics , Protein Interaction Maps , Quercetin/chemistry , Quercetin/pharmacology , SARS-CoV-2/metabolism , Signal Transduction , Sitosterols/chemistry , Sitosterols/pharmacology , Transcriptome/drug effects , Transcriptome/genetics
4.
Molecules ; 27(3)2022 Jan 21.
Article in English | MEDLINE | ID: covidwho-1649980

ABSTRACT

COVID-19 has spread around the world and caused serious public health and social problems. Although several vaccines have been authorized for emergency use, new effective antiviral drugs are still needed. Some repurposed drugs including Chloroquine, Hydroxychloroquine and Remdesivir were immediately used to treat COVID-19 after the pandemic. However, the therapeutic effects of these drugs have not been fully demonstrated in clinical studies. In this paper, we found an antimalarial drug, Naphthoquine, showed good broad-spectrum anti-coronavirus activity. Naphthoquineinhibited HCoV-229E, HCoV-OC43 and SARS-CoV-2 replication in vitro, with IC50 = 2.05 ± 1.44 µM, 5.83 ± 0.74 µM, and 2.01 ± 0.38 µM, respectively. Time-of-addition assay was also performed to explore at which stage Naphthoquine functions during SARS-CoV-2 replication. The results suggested that Naphthoquine may influence virus entry and post-entry replication. Considering the safety of Naphthoquine was even better than that of Chloroquine, we think Naphthoquine has the potential to be used as a broad-spectrum drug for coronavirus infection.


Subject(s)
1-Naphthylamine/analogs & derivatives , Aminoquinolines/pharmacology , Antiviral Agents/pharmacology , Coronavirus/drug effects , SARS-CoV-2/drug effects , 1-Naphthylamine/pharmacology , Animals , Cell Line , Chlorocebus aethiops , Coronavirus 229E, Human/drug effects , Coronavirus NL63, Human/drug effects , Coronavirus OC43, Human/drug effects , Humans , In Vitro Techniques , Vero Cells , Virus Replication/drug effects
5.
J Altern Complement Med ; 26(6): 444-448, 2020 Jun.
Article in English | MEDLINE | ID: covidwho-1637539

ABSTRACT

Editor's Note: For those whose response to COVID-19 includes exploring beyond vaccines, conventional pharmaceuticals, and the watchful or healthy waiting until such tools might arrive, interest in cannabinoids has been high - and controversial. It has already stimulated one journal, the Liebert Cannabis and Cannabinoid Research, to issue a call for papers on COVID-19. The unique place of cannabis in the culture seems to always mark the herb with an exponential asterisk whenever basketed with the other natural health strategies that are both widely used, and as broadly derided. In this invited commentary, JACM Editorial Board member Michelle Sexton, ND starts by describing the multiple immune modulating effects associated with the herb. The University of California San Diego Assistant Adjunct Professor in Anesthesiology then asks: "Given these effects, can phytocannabinoids be either helpful, or harmful for immune competency, in the context of the current COVID-19 pandemic?" A skilled edge-walker, Sexton lets the research fall where it may in wending a path through this evidentiary maze. -John Weeks, Editor-in-Chief, JACM.


Subject(s)
Betacoronavirus/drug effects , Cannabinoids/therapeutic use , Coronavirus Infections/complications , Coronavirus Infections/pathology , Coronavirus/drug effects , Immunocompetence/drug effects , Medical Marijuana/pharmacology , Pneumonia, Viral/complications , Pneumonia, Viral/pathology , Adult , Aged , Aged, 80 and over , COVID-19 , Female , Humans , Immunocompromised Host , Male , Middle Aged , Pandemics , SARS-CoV-2
6.
Nucleic Acids Res ; 50(2): 635-650, 2022 01 25.
Article in English | MEDLINE | ID: covidwho-1621653

ABSTRACT

Coronaviral methyltransferases (MTases), nsp10/16 and nsp14, catalyze the last two steps of viral RNA-cap creation that takes place in cytoplasm. This cap is essential for the stability of viral RNA and, most importantly, for the evasion of innate immune system. Non-capped RNA is recognized by innate immunity which leads to its degradation and the activation of antiviral immunity. As a result, both coronaviral MTases are in the center of scientific scrutiny. Recently, X-ray and cryo-EM structures of both enzymes were solved even in complex with other parts of the viral replication complex. High-throughput screening as well as structure-guided inhibitor design have led to the discovery of their potent inhibitors. Here, we critically summarize the tremendous advancement of the coronaviral MTase field since the beginning of COVID pandemic.


Subject(s)
Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Coronavirus/drug effects , Coronavirus/enzymology , Methyltransferases/antagonists & inhibitors , Methyltransferases/chemistry , Methyltransferases/metabolism , Amino Acid Sequence , Amino Acids/chemistry , Binding Sites , Coronavirus/genetics , Drug Discovery , Humans , Methylation , Models, Molecular , Molecular Conformation , Molecular Structure , Protein Binding , RNA, Viral/chemistry , RNA, Viral/genetics , RNA, Viral/metabolism , Structure-Activity Relationship
7.
Viruses ; 14(1)2022 01 08.
Article in English | MEDLINE | ID: covidwho-1614009

ABSTRACT

Photodynamic inactivation (PDI) employs a photosensitizer, light, and oxygen to create a local burst of reactive oxygen species (ROS) that can inactivate microorganisms. The botanical extract PhytoQuinTM is a powerful photosensitizer with antimicrobial properties. We previously demonstrated that photoactivated PhytoQuin also has antiviral properties against herpes simplex viruses and adenoviruses in a dose-dependent manner across a broad range of sub-cytotoxic concentrations. Here, we report that human coronaviruses (HCoVs) are also susceptible to photodynamic inactivation. Photoactivated-PhytoQuin inhibited the replication of the alphacoronavirus HCoV-229E and the betacoronavirus HCoV-OC43 in cultured cells across a range of sub-cytotoxic doses. This antiviral effect was light-dependent, as we observed minimal antiviral effect of PhytoQuin in the absence of photoactivation. Using RNase protection assays, we observed that PDI disrupted HCoV particle integrity allowing for the digestion of viral RNA by exogenous ribonucleases. Using lentiviruses pseudotyped with the SARS-CoV-2 Spike (S) protein, we once again observed a strong, light-dependent antiviral effect of PhytoQuin, which prevented S-mediated entry into human cells. We also observed that PhytoQuin PDI altered S protein electrophoretic mobility. The PhytoQuin constituent emodin displayed equivalent light-dependent antiviral activity to PhytoQuin in matched-dose experiments, indicating that it plays a central role in PhytoQuin PDI against CoVs. Together, these findings demonstrate that HCoV lipid envelopes and proteins are damaged by PhytoQuin PDI and expands the list of susceptible viruses.


Subject(s)
Antiviral Agents/pharmacology , Coronavirus/drug effects , Photosensitizing Agents/pharmacology , Virus Inactivation/drug effects , Animals , Antiviral Agents/radiation effects , Cell Line , Cell Survival/drug effects , Cricetinae , Emodin/pharmacology , Emodin/radiation effects , Humans , Light , Photosensitizing Agents/radiation effects , Plant Extracts/pharmacology , Plant Extracts/radiation effects , SARS-CoV-2/drug effects , Spike Glycoprotein, Coronavirus/drug effects , Virion/drug effects
8.
mBio ; 12(6): e0334721, 2021 12 21.
Article in English | MEDLINE | ID: covidwho-1599212

ABSTRACT

The world was unprepared for coronavirus disease 2019 (COVID-19) and remains ill-equipped for future pandemics. While unprecedented strides have been made developing vaccines and treatments for COVID-19, there remains a need for highly effective and widely available regimens for ambulatory use for novel coronaviruses and other viral pathogens. We posit that a priority is to develop pan-family drug cocktails to enhance potency, limit toxicity, and avoid drug resistance. We urge cocktail development for all viruses with pandemic potential both in the short term (<1 to 2 years) and longer term with pairs of drugs in advanced clinical testing or repurposed agents approved for other indications. While significant efforts were launched against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), in vitro and in the clinic, many studies employed solo drugs and had disappointing results. Here, we review drug combination studies against SARS-CoV-2 and other viruses and introduce a model-driven approach to assess drug pairs with the highest likelihood of clinical efficacy. Where component agents lack sufficient potency, we advocate for synergistic combinations to achieve therapeutic levels. We also discuss issues that stymied therapeutic progress against COVID-19, including testing of agents with low likelihood of efficacy late in clinical disease and lack of focus on developing virologic surrogate endpoints. There is a need to expedite efficient clinical trials testing drug combinations that could be taken at home by recently infected individuals and exposed contacts as early as possible during the next pandemic, whether caused by a coronavirus or another viral pathogen. The approach herein represents a proactive plan for global viral pandemic preparedness.


Subject(s)
Antiviral Agents/pharmacology , Coronavirus/drug effects , Drug Combinations , Animals , COVID-19/drug therapy , Coronavirus/classification , Coronavirus/pathogenicity , Coronavirus Infections/drug therapy , Humans , Mice , Pandemics/prevention & control , SARS-CoV-2/drug effects
9.
Viruses ; 14(1)2021 12 30.
Article in English | MEDLINE | ID: covidwho-1580401

ABSTRACT

Medicinal chemistry optimization of a previously described stilbene inhibitor of HIV-1, 5350150 (2-(2-(5-nitro-2-thienyl)vinyl)quinoline), led to the identification of the thiazole-5-carboxamide derivative (GPS491), which retained potent anti-HIV-1 activity with reduced toxicity. In this report, we demonstrate that the block of HIV-1 replication by GPS491 is accompanied by a drastic inhibition of viral gene expression (IC50 ~ 0.25 µM), and alterations in the production of unspliced, singly spliced, and multiply spliced HIV-1 RNAs. GPS491 also inhibited the replication of adenovirus and multiple coronaviruses. Low µM doses of GPS491 reduced adenovirus infectious yield ~1000 fold, altered virus early gene expression/viral E1A RNA processing, blocked viral DNA amplification, and inhibited late (hexon) gene expression. Loss of replication of multiple coronaviruses (229E, OC43, SARS-CoV2) upon GPS491 addition was associated with the inhibition of viral structural protein expression and the formation of virus particles. Consistent with the observed changes in viral RNA processing, GPS491 treatment induced selective alterations in the accumulation/phosphorylation/function of splicing regulatory SR proteins. Our study establishes that a compound that impacts the activity of cellular factors involved in RNA processing can prevent the replication of several viruses with minimal effect on cell viability.


Subject(s)
Adenoviridae/drug effects , Antiviral Agents/pharmacology , Coronavirus/drug effects , HIV-1/drug effects , RNA Processing, Post-Transcriptional/drug effects , Thiazoles/pharmacology , Virus Replication/drug effects , Adenoviridae/physiology , Antiviral Agents/chemistry , Cell Line , Coronavirus/classification , Coronavirus/physiology , Gene Expression/drug effects , HIV-1/physiology , Humans , RNA Splicing Factors/metabolism , RNA, Viral/metabolism , Thiazoles/chemistry
10.
Viruses ; 14(1)2021 12 31.
Article in English | MEDLINE | ID: covidwho-1580398

ABSTRACT

We report the discovery of several highly potent small molecules with low-nM potency against severe acute respiratory syndrome coronavirus (SARS-CoV; lowest half-maximal inhibitory concentration (IC50: 13 nM), SARS-CoV-2 (IC50: 23 nM), and Middle East respiratory syndrome coronavirus (MERS-CoV; IC50: 76 nM) in pseudovirus-based assays with excellent selectivity index (SI) values (>5000), demonstrating potential pan-coronavirus inhibitory activities. Some compounds showed 100% inhibition against the cytopathic effects (CPE; IC100) of an authentic SARS-CoV-2 (US_WA-1/2020) variant at 1.25 µM. The most active inhibitors also potently inhibited variants of concern (VOCs), including the UK (B.1.1.7) and South African (B.1.351) variants and the Delta variant (B.1.617.2) originally identified in India in pseudovirus-based assay. Surface plasmon resonance (SPR) analysis with one potent inhibitor confirmed that it binds to the prefusion SARS-CoV-2 spike protein trimer. These small-molecule inhibitors prevented virus-mediated cell-cell fusion. The absorption, distribution, metabolism, and excretion (ADME) data for one of the most active inhibitors, NBCoV1, demonstrated drug-like properties. An in vivo pharmacokinetics (PK) study of NBCoV1 in rats demonstrated an excellent half-life (t1/2) of 11.3 h, a mean resident time (MRT) of 14.2 h, and oral bioavailability. We expect these lead inhibitors to facilitate the further development of preclinical and clinical candidates.


Subject(s)
Antiviral Agents/pharmacology , SARS-CoV-2/drug effects , Virus Internalization/drug effects , Animals , Antiviral Agents/chemistry , Antiviral Agents/pharmacokinetics , Biological Availability , Cell Line , Cell Survival/drug effects , Coronavirus/classification , Coronavirus/drug effects , HIV Fusion Inhibitors/chemistry , HIV Fusion Inhibitors/pharmacokinetics , HIV Fusion Inhibitors/pharmacology , Humans , Protein Binding , Rats , Small Molecule Libraries/chemistry , Small Molecule Libraries/pharmacokinetics , Small Molecule Libraries/pharmacology , Spike Glycoprotein, Coronavirus/antagonists & inhibitors
11.
Sci Rep ; 11(1): 24442, 2021 12 24.
Article in English | MEDLINE | ID: covidwho-1577650

ABSTRACT

Therapeutic interventions targeting viral infections remain a significant challenge for both the medical and scientific communities. While specific antiviral agents have shown success as therapeutics, viral resistance inevitably develops, making many of these approaches ineffective. This inescapable obstacle warrants alternative approaches, such as the targeting of host cellular factors. Respiratory syncytial virus (RSV), the major respiratory pathogen of infants and children worldwide, causes respiratory tract infection ranging from mild upper respiratory tract symptoms to severe life-threatening lower respiratory tract disease. Despite the fact that the molecular biology of the virus, which was originally discovered in 1956, is well described, there is no vaccine or effective antiviral treatment against RSV infection. Here, we demonstrate that targeting host factors, specifically, mTOR signaling, reduces RSV protein production and generation of infectious progeny virus. Further, we show that this approach can be generalizable as inhibition of mTOR kinases reduces coronavirus gene expression, mRNA transcription and protein production. Overall, defining virus replication-dependent host functions may be an effective means to combat viral infections, particularly in the absence of antiviral drugs.


Subject(s)
Coronavirus/metabolism , Respiratory Syncytial Virus, Human/metabolism , TOR Serine-Threonine Kinases/metabolism , Viral Proteins/metabolism , A549 Cells , Coronavirus/drug effects , Coronavirus/genetics , Gene Expression Regulation, Viral/drug effects , Humans , Protein Biosynthesis/drug effects , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , RNA Interference , RNA, Small Interfering/metabolism , Rapamycin-Insensitive Companion of mTOR Protein/antagonists & inhibitors , Rapamycin-Insensitive Companion of mTOR Protein/genetics , Rapamycin-Insensitive Companion of mTOR Protein/metabolism , Regulatory-Associated Protein of mTOR/antagonists & inhibitors , Regulatory-Associated Protein of mTOR/genetics , Regulatory-Associated Protein of mTOR/metabolism , Respiratory Syncytial Virus Infections/drug therapy , Respiratory Syncytial Virus Infections/pathology , Respiratory Syncytial Virus Infections/virology , Respiratory Syncytial Virus, Human/drug effects , Respiratory Syncytial Virus, Human/isolation & purification , TOR Serine-Threonine Kinases/antagonists & inhibitors , TOR Serine-Threonine Kinases/genetics , Viral Proteins/genetics
12.
Sci Rep ; 11(1): 23315, 2021 12 02.
Article in English | MEDLINE | ID: covidwho-1550334

ABSTRACT

The COVID-19 pandemic has highlighted the urgent need for the identification of new antiviral drug therapies for a variety of diseases. COVID-19 is caused by infection with the human coronavirus SARS-CoV-2, while other related human coronaviruses cause diseases ranging from severe respiratory infections to the common cold. We developed a computational approach to identify new antiviral drug targets and repurpose clinically-relevant drug compounds for the treatment of a range of human coronavirus diseases. Our approach is based on graph convolutional networks (GCN) and involves multiscale host-virus interactome analysis coupled to off-target drug predictions. Cell-based experimental assessment reveals several clinically-relevant drug repurposing candidates predicted by the in silico analyses to have antiviral activity against human coronavirus infection. In particular, we identify the MET inhibitor capmatinib as having potent and broad antiviral activity against several coronaviruses in a MET-independent manner, as well as novel roles for host cell proteins such as IRAK1/4 in supporting human coronavirus infection, which can inform further drug discovery studies.


Subject(s)
Antiviral Agents/pharmacology , Coronavirus/drug effects , Coronavirus/metabolism , Drug Development/methods , Drug Repositioning/methods , Benzamides/pharmacology , COVID-19/drug therapy , Cell Line , Computer Simulation , Coronavirus/chemistry , Databases, Pharmaceutical , Drug Discovery/methods , Host-Pathogen Interactions , Humans , Imidazoles/pharmacology , Interleukin-1 Receptor-Associated Kinases/metabolism , SARS-CoV-2/chemistry , SARS-CoV-2/drug effects , SARS-CoV-2/metabolism , SARS-CoV-2/physiology , Triazines/pharmacology
13.
Vet Med Sci ; 7(6): 2434-2439, 2021 11.
Article in English | MEDLINE | ID: covidwho-1525489

ABSTRACT

New viruses are continuously emerging and recently there have been many great concerns on severe acute respiratory syndrome coronavirus (SARS-CoV-2). Nanographene oxide (nanoGO) has received much attention and is widely investigated to be utilised in therapy for infectious diseases by viruses. Thus, antiviral activity of nanoGO was evaluated using the porcine epidemic diarrhoea virus (PEDV), bovine coronavirus (BCoV), and SARS-CoV-2, which are all Alpha- and Beta-coronavirus. In a virus inhibition assay, the three viruses were inhibited by nanoGO in a dose-dependent manner, including attempts in the presence of high serum solution which partially mimicked biological fluid.


Subject(s)
Antiviral Agents/pharmacology , Coronavirus/drug effects , Disinfectants , Graphite/pharmacology , Nanostructures , Humans
14.
Food Funct ; 12(20): 9607-9619, 2021 Oct 19.
Article in English | MEDLINE | ID: covidwho-1500759

ABSTRACT

At the end of 2019, the COVID-19 virus spread worldwide, infecting millions of people. Infectious diseases induced by pathogenic microorganisms such as the influenza virus, hepatitis virus, and Mycobacterium tuberculosis are also a major threat to public health. The high mortality caused by infectious pathogenic microorganisms is due to their strong virulence, which leads to the excessive counterattack by the host immune system and severe inflammatory damage of the immune system. This paper reviews the efficacy, mechanism and related immune regulation of epigallocatechin-3-gallate (EGCG) as an anti-pathogenic microorganism drug. EGCG mainly shows both direct and indirect anti-infection effects. EGCG directly inhibits early infection by interfering with the adsorption on host cells, inhibiting virus replication and reducing bacterial biofilm formation and toxin release; EGCG indirectly inhibits infection by regulating immune inflammation and antioxidation. At the same time, we reviewed the bioavailability and safety of EGCG in vivo. At present, the bioavailability of EGCG can be improved to some extent using nanostructured drug delivery systems and molecular modification technology in combination with other drugs. This study provides a theoretical basis for the development of EGCG as an adjuvant drug for anti-pathogenic microorganisms.


Subject(s)
Anti-Infective Agents/pharmacology , Catechin/analogs & derivatives , Catechin/pharmacology , Immunologic Factors/pharmacology , Animals , Antioxidants/pharmacology , COVID-19/drug therapy , Coronavirus/drug effects , Hepatitis Viruses/drug effects , Humans , Inflammation/drug therapy , Mycobacterium tuberculosis/drug effects , Orthomyxoviridae/drug effects , Oxidative Stress/drug effects , SARS-CoV-2/drug effects , Virus Replication/drug effects
15.
ACS Appl Mater Interfaces ; 13(41): 48469-48477, 2021 Oct 20.
Article in English | MEDLINE | ID: covidwho-1461961

ABSTRACT

The COVID-19 pandemic highlighted the importance of developing surfaces and coatings with antiviral activity. Here, we present, for the first time, peptide-based assemblies that can kill viruses. The minimal inhibitory concentration (MIC) of the assemblies is in the range tens of micrograms per milliliter. This value is 2 orders of magnitude smaller than the MIC of metal nanoparticles. When applied on a surface, by drop casting, the peptide spherical assemblies adhere to the surface and form an antiviral coating against both RNA- and DNA-based viruses including coronavirus. Our results show that the coating reduced the number of T4 bacteriophages (DNA-based virus) by 3 log, compared with an untreated surface and 6 log, when compared with a stock solution. Importantly, we showed that this coating completely inactivated canine coronavirus (RNA-based virus). This peptide-based coating can be useful wherever sterile surfaces are needed to reduce the risk of viral transmission.


Subject(s)
Antiviral Agents/chemistry , Peptides/chemistry , Animals , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Bacteriophages/drug effects , COVID-19/drug therapy , COVID-19/virology , Coronavirus/drug effects , Coronavirus/isolation & purification , Coronavirus Infections/drug therapy , Coronavirus Infections/virology , Dihydroxyphenylalanine/chemistry , Dog Diseases/drug therapy , Dog Diseases/virology , Dogs , Humans , Metal Nanoparticles/chemistry , Peptides/pharmacology , Peptides/therapeutic use , SARS-CoV-2/isolation & purification , Virus Inactivation/drug effects
16.
Repert. med. cir ; 29((Núm. Supl.1.)): 1-9, 2020. Il., dibujos, graf.
Article in Spanish | WHO COVID, LILACS (Americas) | ID: covidwho-1456661

ABSTRACT

Conscientes de la emergencia sanitaria mundial desencadenada por el COVID-19 y la imperiosa necesidad de tomar decisiones tanto tempranas como efectivas, nuestro grupo desarrolló esta guía dirigida a la interpretación rápida y enfocada del electrocardiograma convencional de 12 derivaciones en pacientes con infección por SARS-CoV-2 en quienes se plantea inicio de tratamiento farmacológico. Dadas las alternativas terapéuticas que se están implementando de manera precoz para tener un impacto en la sobrevida de los pacientes, es imperioso limitar el número de efectos adversos que se pueden desencadenar en el desarrollo del tratamiento intrahospitalario como ambulatorio. Somos a su vez conscientes de que la coyuntura actual demanda toma de decisiones costo-efectivas y ágiles en el menor tiempo posible. Por lo anterior, gestamos esta guía rápida para facilitarle al personal médico involucrado en el manejo de estos pacientes (internistas, cardiólogos, intensivistas, infectologos, etc.) la interpretación y valoración de los tópicos más relevantes en electrocardiografía para limitar el número de posibles complicaciones en sus pacientes. El objetivo de dicha guía es acortar tiempos de atención, inicio temprano de terapia farmacológica basado en su juicio clínico y limitar al máximo posibles complicaciones y/o efectos adversos que retrasen el punto crítico terapéutico infeccioso. Esperamos facilitar a ustedes y su grupo de trabajo la toma de decisiones, basado en el uso costo-efectivo del electrocardiograma. No obstante, es importante recordar que toda decisión médica es un ejercicio riguroso, científico e integral basado en cada caso en particular. El electrocardiograma la ayudará a reforzar sus decisiones, así como a seguir a los pacientes que puedan presentar posibles complicaciones. Lo invitamos a que guarde esta guía rápida en sus dispositivos digitales y en cada momento que considere inicio de terapia farmacológica valore lo que en ella se indica.


Subject(s)
Humans , Male , Female , Coronavirus/drug effects , Electrocardiography , Drug Therapy
17.
Molecules ; 25(8)2020 Apr 18.
Article in English | MEDLINE | ID: covidwho-1450861

ABSTRACT

(1) Background: Viral respiratory infections cause life-threatening diseases in millions of people worldwide every year. Human coronavirus and several picornaviruses are responsible for worldwide epidemic outbreaks, thus representing a heavy burden to their hosts. In the absence of specific treatments for human viral infections, natural products offer an alternative in terms of innovative drug therapies. (2) Methods: We analyzed the antiviral properties of the leaves and stem bark of the mulberry tree (Morus spp.). We compared the antiviral activity of Morus spp. on enveloped and nonenveloped viral pathogens, such as human coronavirus (HCoV 229E) and different members of the Picornaviridae family-human poliovirus 1, human parechovirus 1 and 3, and human echovirus 11. The antiviral activity of 12 water and water-alcohol plant extracts of the leaves and stem bark of three different species of mulberry-Morus alba var. alba, Morus alba var. rosa, and Morus rubra-were evaluated. We also evaluated the antiviral activities of kuwanon G against HCoV-229E. (3) Results: Our results showed that several extracts reduced the viral titer and cytopathogenic effects (CPE). Leaves' water-alcohol extracts exhibited maximum antiviral activity on human coronavirus, while stem bark and leaves' water and water-alcohol extracts were the most effective on picornaviruses. (4) Conclusions: The analysis of the antiviral activities of Morus spp. offer promising applications in antiviral strategies.


Subject(s)
Antiviral Agents/pharmacology , Coronavirus/drug effects , Morus/chemistry , Plant Extracts/pharmacology , Respiratory Tract Infections/drug therapy , Antiviral Agents/therapeutic use , Cell Line , Cytopathogenic Effect, Viral/drug effects , Flavonoids/pharmacology , Humans , Mass Spectrometry , Microbial Sensitivity Tests , Picornaviridae/drug effects , Plant Bark/chemistry , Plant Extracts/therapeutic use , Plant Leaves/chemistry
18.
Virol J ; 17(1): 136, 2020 09 09.
Article in English | MEDLINE | ID: covidwho-1435256

ABSTRACT

BACKGROUND: Coronaviruses (CoVs) were long thought to only cause mild respiratory and gastrointestinal symptoms in humans but outbreaks of Middle East Respiratory Syndrome (MERS)-CoV, Severe Acute Respiratory Syndrome (SARS)-CoV-1, and the recently identified SARS-CoV-2 have cemented their zoonotic potential and their capacity to cause serious morbidity and mortality, with case fatality rates ranging from 4 to 35%. Currently, no specific prophylaxis or treatment is available for CoV infections. Therefore we investigated the virucidal and antiviral potential of Echinacea purpurea (Echinaforce®) against human coronavirus (HCoV) 229E, highly pathogenic MERS- and SARS-CoVs, as well as the newly identified SARS-CoV-2, in vitro. METHODS: To evaluate the antiviral potential of the extract, we pre-treated virus particles and cells and evaluated remaining infectivity by limited dilution. Furthermore, we exposed cells to the extract after infection to further evaluate its potential as a prophylaxis and treatment against coronaviruses. We also determined the protective effect of Echinaforce® in re-constituted nasal epithelium. RESULTS: In the current study, we found that HCoV-229E was irreversibly inactivated when exposed to Echinaforce® at 3.2 µg/ml IC50. Pre-treatment of cell lines, however, did not inhibit infection with HCoV-229E and post-infection treatment had only a marginal effect on virus propagation at 50 µg/ml. However, we did observe a protective effect in an organotypic respiratory cell culture system by exposing pre-treated respiratory epithelium to droplets of HCoV-229E, imitating a natural infection. The observed virucidal activity of Echinaforce® was not restricted to common cold coronaviruses, as both SARS-CoV-1 and MERS-CoVs were inactivated at comparable concentrations. Finally, the causative agent of COVID-19, SARS-CoV-2 was also inactivated upon treatment with 50µg/ml Echinaforce®. CONCLUSIONS: These results show that Echinaforce® is virucidal against HCoV-229E, upon direct contact and in an organotypic cell culture model. Furthermore, MERS-CoV and both SARS-CoV-1 and SARS-CoV-2 were inactivated at similar concentrations of the extract. Therefore we hypothesize that Echinacea purpurea preparations, such as Echinaforce®, could be effective as prophylactic treatment for all CoVs due to their structural similarities.


Subject(s)
Antiviral Agents/pharmacology , Betacoronavirus/drug effects , Coronavirus 229E, Human/drug effects , Coronavirus Infections/drug therapy , Coronavirus/drug effects , Plant Extracts/pharmacology , Plant Extracts/therapeutic use , Animals , COVID-19 , Cell Line , Chlorocebus aethiops , Common Cold/drug therapy , Common Cold/virology , Coronavirus Infections/virology , Humans , Middle East Respiratory Syndrome Coronavirus/drug effects , Pandemics , Pneumonia, Viral/drug therapy , Pneumonia, Viral/virology , RNA Viruses/drug effects , Randomized Controlled Trials as Topic , SARS-CoV-2 , Severe Acute Respiratory Syndrome/drug therapy , Severe Acute Respiratory Syndrome/virology , Vero Cells
19.
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
20.
Food Funct ; 12(20): 9607-9619, 2021 Oct 19.
Article in English | MEDLINE | ID: covidwho-1434159

ABSTRACT

At the end of 2019, the COVID-19 virus spread worldwide, infecting millions of people. Infectious diseases induced by pathogenic microorganisms such as the influenza virus, hepatitis virus, and Mycobacterium tuberculosis are also a major threat to public health. The high mortality caused by infectious pathogenic microorganisms is due to their strong virulence, which leads to the excessive counterattack by the host immune system and severe inflammatory damage of the immune system. This paper reviews the efficacy, mechanism and related immune regulation of epigallocatechin-3-gallate (EGCG) as an anti-pathogenic microorganism drug. EGCG mainly shows both direct and indirect anti-infection effects. EGCG directly inhibits early infection by interfering with the adsorption on host cells, inhibiting virus replication and reducing bacterial biofilm formation and toxin release; EGCG indirectly inhibits infection by regulating immune inflammation and antioxidation. At the same time, we reviewed the bioavailability and safety of EGCG in vivo. At present, the bioavailability of EGCG can be improved to some extent using nanostructured drug delivery systems and molecular modification technology in combination with other drugs. This study provides a theoretical basis for the development of EGCG as an adjuvant drug for anti-pathogenic microorganisms.


Subject(s)
Anti-Infective Agents/pharmacology , Catechin/analogs & derivatives , Catechin/pharmacology , Immunologic Factors/pharmacology , Animals , Antioxidants/pharmacology , COVID-19/drug therapy , Coronavirus/drug effects , Hepatitis Viruses/drug effects , Humans , Inflammation/drug therapy , Mycobacterium tuberculosis/drug effects , Orthomyxoviridae/drug effects , Oxidative Stress/drug effects , SARS-CoV-2/drug effects , Virus Replication/drug effects
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