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1.
Int J Biol Sci ; 18(12): 4744-4755, 2022.
Article in English | MEDLINE | ID: covidwho-1954694

ABSTRACT

Viruses exploit the host lipid metabolism machinery to achieve efficient replication. We herein characterize the lipids profile reprogramming in vitro and in vivo using liquid chromatography-mass spectrometry-based untargeted lipidomics. The lipidome of SARS-CoV-2-infected Caco-2 cells was markedly different from that of mock-infected samples, with most of the changes involving downregulation of ceramides. In COVID-19 patients' plasma samples, a total of 54 lipids belonging to 12 lipid classes that were significantly perturbed compared to non-infected control subjects' plasma samples were identified. Among these 12 lipid classes, ether-linked phosphatidylcholines, ether-linked phosphatidylethanolamines, phosphatidylcholines, and ceramides were the four most perturbed. Pathway analysis revealed that the glycerophospholipid, sphingolipid, and ether lipid metabolisms pathway were the most significantly perturbed host pathways. Phosphatidic acid phosphatases (PAP) were involved in all three pathways and PAP-1 deficiency significantly suppressed SARS-CoV-2 replication. siRNA knockdown of LPIN2 and LPIN3 resulted in significant reduction of SARS-CoV-2 load. In summary, these findings characterized the host lipidomic changes upon SARS-CoV-2 infection and identified PAP-1 as a potential target for intervention for COVID-19.


Subject(s)
COVID-19 , SARS-CoV-2 , Caco-2 Cells , Ceramides , Ethers , Glycerophospholipids , Humans , Lipid Metabolism , Phosphatidate Phosphatase/genetics , Phosphatidate Phosphatase/metabolism , Phosphatidylcholines/metabolism , Phosphatidylethanolamines/metabolism
2.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-325229

ABSTRACT

The 2019 novel respiratory virus (SARS-CoV-2) causes COVID-19 with rapid global socioeconomic disruptions and disease burden to healthcare. The current COVID-19 and previous emerging virus outbreaks highlight the urgent need for broad-spectrum antivirals. Here, we showed that a defensin-like peptide P9R exhibited potent antiviral activity against pH-dependent viruses that require endosomal acidification for virus-host membrane fusion, including the enveloped coronaviruses (SARS-CoV-2, SARS-CoV and MERS-CoV), the pandemic A(H1N1)pdm09 virus, avian influenza A(H7N9) virus, and the non-enveloped rhinovirus. P9R could significantly protect mice from lethal challenge by A(H1N1)pdm09 virus and showed low possibility to cause drug-resistance virus. Mechanistic studies indicated that the antiviral activity of P9R depended on the direct binding to viruses and the inhibition of virus-host endosomal acidification, which provides a new concept that virus-binding alkaline peptides could broadly inhibit pH-dependent viruses. These results suggest that the dual-functional virus- and host-targeting P9R could be a promising candidate for combating pH-dependent respiratory viruses.Authors Hanjun Zhao, Kelvin K. W. To, and Kong-Hung Sze contributed equally to this work.

3.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-324816

ABSTRACT

COVID-19 pandemic is the third zoonotic coronavirus (CoV) outbreak of the century after severe acute respiratory syndrome (SARS) in 2003 and Middle East respiratory syndrome (MERS) since 2012. Treatment options for CoVs are largely lacking. Here, we show that clofazimine, an anti-leprosy drug with a favorable safety and pharmacokinetics profile, possesses pan-coronaviral inhibitory activity, and can antagonize SARS-CoV-2 replication in multiple in vitro systems, including the human embryonic stem cell-derived cardiomyocytes and ex vivo lung cultures. The FDA-approved molecule was found to inhibit multiple steps of viral replication, suggesting multiple underlying antiviral mechanisms. In a hamster model of SARS-CoV-2 pathogenesis, prophylactic or therapeutic administration of clofazimine significantly reduced viral load in the lung and fecal viral shedding, and also prevented cytokine storm associated with viral infection. Additionally, clofazimine exhibited synergy when administered with remdesivir. Since clofazimine is orally bioavailable and has a comparatively low manufacturing cost, it is an attractive clinical candidate for outpatient treatment and remdesivir-based combinatorial therapy for hospitalized COVID-19 patients, particularly in developing countries. Taken together, our data provide evidence that clofazimine may have a role in the control of the current pandemic SARS-CoV-2, endemic MERS-CoV in the Middle East, and, possibly most importantly, emerging CoVs of the future.

4.
J Gen Virol ; 102(5)2021 05.
Article in English | MEDLINE | ID: covidwho-1218064

ABSTRACT

Host cell lipids play a pivotal role in the pathogenesis of respiratory virus infection. However, a direct comparison of the lipidomic profile of influenza virus and rhinovirus infections is lacking. In this study, we first compared the lipid profile of influenza virus and rhinovirus infection in a bronchial epithelial cell line. Most lipid features were downregulated for both influenza virus and rhinovirus, especially for the sphingomyelin features. Pathway analysis showed that sphingolipid metabolism was the most perturbed pathway. Functional study showed that bacterial sphingomyelinase suppressed influenza virus and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication, but promoted rhinovirus replication. These findings suggest that sphingomyelin pathway can be a potential target for antiviral therapy, but should be carefully evaluated as it has opposite effects on different respiratory viruses. Furthermore, the differential effect of sphingomyelinase on rhinovirus and influenza virus may explain the interference between rhinovirus and influenza virus infection.


Subject(s)
Orthomyxoviridae/drug effects , Rhinovirus/drug effects , SARS-CoV-2/drug effects , Sphingomyelins/pharmacology , Animals , Bronchial Diseases/virology , COVID-19/drug therapy , Cell Line , Dogs , Epithelial Cells/virology , Humans , Influenza, Human , Lipidomics , Madin Darby Canine Kidney Cells , Orthomyxoviridae Infections/drug therapy , Sphingomyelin Phosphodiesterase , Virus Replication/drug effects
5.
Nature ; 593(7859): 418-423, 2021 05.
Article in English | MEDLINE | ID: covidwho-1137788

ABSTRACT

The COVID-19 pandemic is the third outbreak this century of a zoonotic disease caused by a coronavirus, following the emergence of severe acute respiratory syndrome (SARS) in 20031 and Middle East respiratory syndrome (MERS) in 20122. Treatment options for coronaviruses are limited. Here we show that clofazimine-an anti-leprosy drug with a favourable safety profile3-possesses inhibitory activity against several coronaviruses, and can antagonize the replication of SARS-CoV-2 and MERS-CoV in a range of in vitro systems. We found that this molecule, which has been approved by the US Food and Drug Administration, inhibits cell fusion mediated by the viral spike glycoprotein, as well as activity of the viral helicase. Prophylactic or therapeutic administration of clofazimine in a hamster model of SARS-CoV-2 pathogenesis led to reduced viral loads in the lung and viral shedding in faeces, and also alleviated the inflammation associated with viral infection. Combinations of clofazimine and remdesivir exhibited antiviral synergy in vitro and in vivo, and restricted viral shedding from the upper respiratory tract. Clofazimine, which is orally bioavailable and comparatively cheap to manufacture, is an attractive clinical candidate for the treatment of outpatients and-when combined with remdesivir-in therapy for hospitalized patients with COVID-19, particularly in contexts in which costs are an important factor or specialized medical facilities are limited. Our data provide evidence that clofazimine may have a role in the control of the current pandemic of COVID-19 and-possibly more importantly-in dealing with coronavirus diseases that may emerge in the future.


Subject(s)
Antiviral Agents/pharmacology , Clofazimine/pharmacology , Coronavirus/classification , Coronavirus/drug effects , SARS-CoV-2/drug effects , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/pharmacology , Adenosine Monophosphate/therapeutic use , Alanine/analogs & derivatives , Alanine/pharmacology , Alanine/therapeutic use , Animals , Anti-Inflammatory Agents/pharmacokinetics , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/therapeutic use , Antiviral Agents/pharmacokinetics , Antiviral Agents/therapeutic use , Biological Availability , Cell Fusion , Cell Line , Clofazimine/pharmacokinetics , Clofazimine/therapeutic use , Coronavirus/growth & development , Coronavirus/pathogenicity , Cricetinae , DNA Helicases/antagonists & inhibitors , Drug Synergism , Female , Humans , Life Cycle Stages/drug effects , Male , Mesocricetus , Pre-Exposure Prophylaxis , SARS-CoV-2/growth & development , Species Specificity , Spike Glycoprotein, Coronavirus/antagonists & inhibitors , Transcription, Genetic/drug effects , Transcription, Genetic/genetics
6.
Res Sq ; 2020 Oct 07.
Article in English | MEDLINE | ID: covidwho-869425

ABSTRACT

COVID-19 pandemic is the third zoonotic coronavirus (CoV) outbreak of the century after severe acute respiratory syndrome (SARS) in 2003 and Middle East respiratory syndrome (MERS) since 2012. Treatment options for CoVs are largely lacking. Here, we show that clofazimine, an anti-leprosy drug with a favorable safety and pharmacokinetics profile, possesses pan-coronaviral inhibitory activity, and can antagonize SARS-CoV-2 replication in multiple in vitro systems, including the human embryonic stem cell-derived cardiomyocytes and ex vivo lung cultures. The FDA-approved molecule was found to inhibit multiple steps of viral replication, suggesting multiple underlying antiviral mechanisms. In a hamster model of SARS-CoV-2 pathogenesis, prophylactic or therapeutic administration of clofazimine significantly reduced viral load in the lung and fecal viral shedding, and also prevented cytokine storm associated with viral infection. Additionally, clofazimine exhibited synergy when administered with remdesivir. Since clofazimine is orally bioavailable and has a comparatively low manufacturing cost, it is an attractive clinical candidate for outpatient treatment and remdesivir-based combinatorial therapy for hospitalized COVID-19 patients, particularly in developing countries. Taken together, our data provide evidence that clofazimine may have a role in the control of the current pandemic SARS-CoV-2, endemic MERS-CoV in the Middle East, and, possibly most importantly, emerging CoVs of the future.

7.
Sci Adv ; 6(35): eaba7910, 2020 08.
Article in English | MEDLINE | ID: covidwho-760200

ABSTRACT

Targeting a universal host protein exploited by most viruses would be a game-changing strategy that offers broad-spectrum solution and rapid pandemic control including the current COVID-19. Here, we found a common YxxØ-motif of multiple viruses that exploits host AP2M1 for intracellular trafficking. A library chemical, N-(p-amylcinnamoyl)anthranilic acid (ACA), was identified to interrupt AP2M1-virus interaction and exhibit potent antiviral efficacy against a number of viruses in vitro and in vivo, including the influenza A viruses (IAVs), Zika virus (ZIKV), human immunodeficiency virus, and coronaviruses including MERS-CoV and SARS-CoV-2. YxxØ mutation, AP2M1 depletion, or disruption by ACA causes incorrect localization of viral proteins, which is exemplified by the failure of nuclear import of IAV nucleoprotein and diminished endoplasmic reticulum localization of ZIKV-NS3 and enterovirus-A71-2C proteins, thereby suppressing viral replication. Our study reveals an evolutionarily conserved mechanism of protein-protein interaction between host and virus that can serve as a broad-spectrum antiviral target.


Subject(s)
Adaptor Proteins, Vesicular Transport/metabolism , Antiviral Agents/pharmacology , Cinnamates/pharmacology , Coronavirus Infections/drug therapy , HIV Infections/drug therapy , Influenza, Human/drug therapy , Pneumonia, Viral/drug therapy , ortho-Aminobenzoates/pharmacology , A549 Cells , Animals , Betacoronavirus/drug effects , Binding Sites/genetics , COVID-19 , Cell Line, Tumor , Chlorocebus aethiops , Coronavirus Infections/pathology , Dogs , HEK293 Cells , HIV Infections/pathology , HIV-1/drug effects , Host-Pathogen Interactions/drug effects , Humans , Influenza A virus/drug effects , Influenza, Human/pathology , Madin Darby Canine Kidney Cells , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Knockout , Middle East Respiratory Syndrome Coronavirus/drug effects , Pandemics , Pneumonia, Viral/pathology , Protein Binding/genetics , Protein Transport/drug effects , RNA, Viral/genetics , Receptor, Interferon alpha-beta/genetics , SARS-CoV-2 , Transforming Growth Factor beta1/metabolism , Vero Cells , Virus Replication/drug effects , Zika Virus/drug effects , Zika Virus Infection/pathology
8.
Nat Commun ; 11(1): 4252, 2020 08 25.
Article in English | MEDLINE | ID: covidwho-741685

ABSTRACT

The 2019 novel respiratory virus (SARS-CoV-2) causes COVID-19 with rapid global socioeconomic disruptions and disease burden to healthcare. The COVID-19 and previous emerging virus outbreaks highlight the urgent need for broad-spectrum antivirals. Here, we show that a defensin-like peptide P9R exhibited potent antiviral activity against pH-dependent viruses that require endosomal acidification for virus infection, including the enveloped pandemic A(H1N1)pdm09 virus, avian influenza A(H7N9) virus, coronaviruses (SARS-CoV-2, MERS-CoV and SARS-CoV), and the non-enveloped rhinovirus. P9R can significantly protect mice from lethal challenge by A(H1N1)pdm09 virus and shows low possibility to cause drug-resistant virus. Mechanistic studies indicate that the antiviral activity of P9R depends on the direct binding to viruses and the inhibition of virus-host endosomal acidification, which provides a proof of concept that virus-binding alkaline peptides can broadly inhibit pH-dependent viruses. These results suggest that the dual-functional virus- and host-targeting P9R can be a promising candidate for combating pH-dependent respiratory viruses.


Subject(s)
Antiviral Agents/pharmacology , Coronavirus/drug effects , Influenza A virus/drug effects , Peptides/pharmacology , Amino Acid Sequence , Animals , Antiviral Agents/chemistry , Antiviral Agents/metabolism , Antiviral Agents/therapeutic use , Cell Line , Endosomes/chemistry , Endosomes/drug effects , Female , Humans , Hydrogen-Ion Concentration , Influenza A virus/metabolism , Mice , Mice, Inbred BALB C , Orthomyxoviridae Infections/drug therapy , Orthomyxoviridae Infections/metabolism , Peptides/chemistry , Peptides/metabolism , Peptides/therapeutic use , Protein Binding , Protein Conformation , Rhinovirus/drug effects , Rhinovirus/metabolism , Viral Load/drug effects , Virus Replication/drug effects
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