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1.
Int J Mol Sci ; 23(13)2022 Jul 01.
Article in English | MEDLINE | ID: covidwho-1917524

ABSTRACT

Virus-cell fusion is the key step for viral infection in host cells. Studies on virus binding and fusion with host cells are important for understanding the virus-host interaction and viral pathogenesis for the discovery of antiviral drugs. In this review, we focus on the virus-cell fusions induced by the two major pandemic viruses, including the influenza virus and SARS-CoV-2. We further compare the cell fusions induced by the influenza virus and SARS-CoV-2, especially the pH-dependent fusion of the influenza virus and the fusion of SARS-CoV-2 in the type-II transmembrane serine protease 2 negative (TMPRSS2-) cells with syncytia formation. Finally, we present the development of drugs used against SARA-CoV-2 and the influenza virus through the discovery of anti-fusion drugs and the prevention of pandemic respiratory viruses.


Subject(s)
COVID-19 , Orthomyxoviridae , Cell Fusion , Humans , Orthomyxoviridae/metabolism , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/metabolism , Virus Internalization
2.
Cell Discov ; 8(1): 62, 2022 Jun 30.
Article in English | MEDLINE | ID: covidwho-1908152

ABSTRACT

The emergence of highly transmissible SARS-CoV-2 variants has led to the waves of the resurgence of COVID-19 cases. Effective antivirals against variants are required. Here we demonstrate that a human-derived peptide 4H30 has broad antiviral activity against the ancestral virus and four Variants of Concern (VOCs) in vitro. Mechanistically, 4H30 can inhibit three distinct steps of the SARS-CoV-2 life cycle. Specifically, 4H30 blocks viral entry by clustering SARS-CoV-2 virions; prevents membrane fusion by inhibiting endosomal acidification; and inhibits the release of virions by cross-linking SARS-CoV-2 with cellular glycosaminoglycans. In vivo studies show that 4H30 significantly reduces the lung viral titers in hamsters, with a more potent reduction for the Omicron variant than the Delta variant. This is likely because the entry of the Omicron variant mainly relies on the endocytic pathway which is targeted by 4H30. Moreover, 4H30 reduces syncytia formation in infected hamster lungs. These findings provide a proof of concept that a single antiviral can inhibit viral entry, fusion, and release.

4.
Adv Exp Med Biol ; 1366: 137-153, 2022.
Article in English | MEDLINE | ID: covidwho-1782744

ABSTRACT

With the increasing global human population, travel, and socioeconomic activities, more and more novel pathogenic viruses will emerge or re-emerge. While more than 260 viruses are known to infect humans, only a small minority of these viral diseases are treatable by clinically approved antiviral drugs. Apart from these identified viruses, new emerging viruses and drug-resistant viruses are also important challenges to our public health and healthcare systems. The COVID-19 and influenza pandemics remind us the importance of getting broad-spectrum antivirals against emerging and re-emerging respiratory viruses. Broad-spectrum antivirals against different viral families for fighting the currently known viruses and novel emerging viruses are urgently needed. Viral entry is the universal first step for viral infection, and therefore is a promising target for identifying broad-spectrum antivirals. In this chapter, we mainly focus on discussing the risks of respiratory viruses, the challenge of finding broad-spectrum antivirals, the entry processes of respiratory viruses, the current studies on broad-spectrum entry inhibitors for respiratory viruses, and the directions for discovering broad-spectrum antivirals in the future.


Subject(s)
COVID-19 , Virus Diseases , Viruses , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Humans , Virus Diseases/drug therapy , Virus Internalization
5.
Emerg Microbes Infect ; 11(1): 926-937, 2022 Dec.
Article in English | MEDLINE | ID: covidwho-1730559

ABSTRACT

Pandemic influenza virus and SARS-CoV-2 vaiants have posed major global threats to public health. Broad-spectrum antivirals blocking viral entry can be an effective strategy for combating these viruses. Here, we demonstrate a frog-defensin-derived basic peptide (FBP), which broadly inhibits the influenza virus by binding to haemagglutinin so as to block low pH-induced HA-mediated fusion and antagonizes endosomal acidification to inhibit the influenza virus. Moreover, FBP can bind to the SARS-CoV-2 spike to block spike-mediated cell-cell fusion in 293T/ACE2 cells endocytosis. Omicron spike shows a weak cell-cell fusion mediated by TMPRSS2 in Calu3 cells, making the Omicron variant sensitive to endosomal inhibitors. In vivo studies show that FBP broadly inhibits the A(H1N1)pdm09 virus in mice and SARS-CoV-2 (HKU001a and Delta)in hamsters. Notably, FBP shows significant inhibition of Omicron variant replication even though it has a high number of mutations in spike. In conclusion, these results suggest that virus-targeting FBP with a high barrier to drug resistance can be an effective entry-fusion inhibitor against influenza virus and SARS-CoV-2 in vivo.


Subject(s)
COVID-19 , Influenza A Virus, H1N1 Subtype , Animals , COVID-19/drug therapy , Mice , Peptides , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism
6.
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.

7.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-325226

ABSTRACT

So far, effective antivirals have not been widely available for treating COVID-19. In this study, we identify a dual-functional cross-linking peptide 8P9R which can inhibit the two entry pathways (endocytic pathway and TMPRSS2-mediated surface pathway) of SARS-CoV-2 in cells. The endosomal acidification inhibitors (8P9R and chloroquine) can synergistically enhance the activity of arbidol, a spike-ACE2 fusion inhibitor, against SARS-CoV-2 and SARS-CoV in cells. In vivo studies indicate that 8P9R or the combination of repurposed drugs (arbidol, chloroquine and camostat which is a TMPRSS2 inhibitor), simultaneously interfering with the two entry pathways of coronavirus, can significantly suppress SARS-CoV-2 replication in hamsters and SARS-CoV in mice. Here, we use drug combination (arbidol, chloroquine, and camostat) and a dual-functional 8P9R to demonstrate that blocking the two entry pathways of coronavirus can be a promising and achievable approach for inhibiting SARS-CoV-2 replication in vivo. Cocktail therapy of these drug combinations should be considered in treatment trials for COVID-19.

8.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-325225

ABSTRACT

Influenza virus, coronavirus, and drug-resistant viruses are long-term threats to public health because of lacking effective antivirals. Thus, chemicals with broad-spectrum antiviral activities and low possibility to induce drug resistance are urgently needed. Here, we identify a peptidic inhibitor P16 significantly inhibiting influenza A/B virus by binding to HA to block viral fusion. Moreover, P16 antagonizes endosomal acidification to suppress influenza virus and SARS-CoV-2 entry through the endocytic pathway. Importantly, endosomal acidification inhibitor P16 or chloroquine can broadly inhibit A(H1N1) virus, SARS-CoV and SARS-CoV-2 replication in mice and hamsters when administrated through intranasal inoculation or atomization inhalation, contrary to reported treatment failure by systemic route. Chloroquine can significantly inhibit SARS-CoV-2 replication in ex vivo human lung tissues. In conclusion, endosomal acidification inhibitors (P16 and chloroquine) can broadly inhibit influenza virus and coronavirus replication in vivo, which supports atomization inhalation of chloroquine for treating coronavirus and influenza patients in clinical trials.

9.
Emerg Microbes Infect ; 11(1): 277-283, 2022 Dec.
Article in English | MEDLINE | ID: covidwho-1585239

ABSTRACT

The novel SARS-CoV-2 Omicron variant (B.1.1.529), first found in early November 2021, has sparked considerable global concern and it has >50 mutations, many of which are known to affect transmissibility or cause immune escape. In this study, we sought to investigate the virological characteristics of the Omicron variant and compared it with the Delta variant which has dominated the world since mid-2021. Omicron variant replicated more slowly than the Delta variant in transmembrane serine protease 2 (TMPRSS2)-overexpressing VeroE6 (VeroE6/TMPRSS2) cells. Notably, the Delta variant replicated well in Calu3 cell line which has robust TMPRSS2 expression, while the Omicron variant replicated poorly in this cell line. Competition assay showed that Delta variant outcompeted Omicron variant in VeroE6/TMPRSS2 and Calu3 cells. To confirm the difference in entry pathway between the Omicron and Delta variants, we assessed the antiviral effect of bafilomycin A1, chloroquine (inhibiting endocytic pathway), and camostat (inhibiting TMPRSS2 pathway). Camostat potently inhibited the Delta variant but not the Omicron variant, while bafilomycin A1 and chloroquine could inhibit both Omicron and Delta variants. Moreover, the Omicron variant also showed weaker cell-cell fusion activity when compared with Delta variant in VeroE6/TMPRSS2 cells. Collectively, our results suggest that Omicron variant infection is not enhanced by TMPRSS2 but is largely mediated via the endocytic pathway. The difference in entry pathway between Omicron and Delta variants may have an implication on the clinical manifestations or disease severity.


Subject(s)
COVID-19/virology , SARS-CoV-2/physiology , Serine Endopeptidases/metabolism , Virus Internalization , Virus Replication , Animals , Carcinoma, Non-Small-Cell Lung/pathology , Cell Line, Tumor , Chlorocebus aethiops , Chloroquine/pharmacology , Endocytosis/drug effects , Esters/pharmacology , Guanidines/pharmacology , Humans , Immune Evasion , Lung Neoplasms/pathology , Macrolides/pharmacology , Recombinant Proteins/metabolism , SARS-CoV-2/genetics , Vero Cells , Virus Cultivation , Virus Internalization/drug effects , Whole Genome Sequencing
10.
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
11.
Nat Commun ; 12(1): 1517, 2021 03 09.
Article in English | MEDLINE | ID: covidwho-1125914

ABSTRACT

Up to date, effective antivirals have not been widely available for treating COVID-19. In this study, we identify a dual-functional cross-linking peptide 8P9R which can inhibit the two entry pathways (endocytic pathway and TMPRSS2-mediated surface pathway) of SARS-CoV-2 in cells. The endosomal acidification inhibitors (8P9R and chloroquine) can synergistically enhance the activity of arbidol, a spike-ACE2 fusion inhibitor, against SARS-CoV-2 and SARS-CoV in cells. In vivo studies indicate that 8P9R or the combination of repurposed drugs (umifenovir also known as arbidol, chloroquine and camostat which is a TMPRSS2 inhibitor), simultaneously interfering with the two entry pathways of coronaviruses, can significantly suppress SARS-CoV-2 replication in hamsters and SARS-CoV in mice. Here, we use drug combination (arbidol, chloroquine, and camostat) and a dual-functional 8P9R to demonstrate that blocking the two entry pathways of coronavirus can be a promising and achievable approach for inhibiting SARS-CoV-2 replication in vivo. Cocktail therapy of these drug combinations should be considered in treatment trials for COVID-19.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , Drug Repositioning , Peptides/pharmacology , SARS-CoV-2/drug effects , Virus Internalization/drug effects , Animals , COVID-19/virology , Chlorocebus aethiops , Chloroquine/pharmacology , Drug Discovery , Female , HEK293 Cells , Humans , Indoles/pharmacology , Mice , Mice, Inbred BALB C , Serine Endopeptidases/metabolism , Vero Cells
12.
Cell ; 184(8): 2212-2228.e12, 2021 04 15.
Article in English | MEDLINE | ID: covidwho-1116430

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can cause acute respiratory disease and multiorgan failure. Finding human host factors that are essential for SARS-CoV-2 infection could facilitate the formulation of treatment strategies. Using a human kidney cell line-HK-2-that is highly susceptible to SARS-CoV-2, we performed a genome-wide RNAi screen and identified virus dependency factors (VDFs), which play regulatory roles in biological pathways linked to clinical manifestations of SARS-CoV-2 infection. We found a role for a secretory form of SARS-CoV-2 receptor, soluble angiotensin converting enzyme 2 (sACE2), in SARS-CoV-2 infection. Further investigation revealed that SARS-CoV-2 exploits receptor-mediated endocytosis through interaction between its spike with sACE2 or sACE2-vasopressin via AT1 or AVPR1B, respectively. Our identification of VDFs and the regulatory effect of sACE2 on SARS-CoV-2 infection shed insight into pathogenesis and cell entry mechanisms of SARS-CoV-2 as well as potential treatment strategies for COVID-19.


Subject(s)
Angiotensin-Converting Enzyme 2/immunology , Host Microbial Interactions/immunology , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Vasopressins/immunology , Virus Internalization , COVID-19/immunology , COVID-19/virology , Cell Line , Humans , Protein Binding
13.
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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