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Book ; Online ; Thesis: Proteolytic activation of Zaire ebolavirus and SARS-CoV-2 class I membrane fusion proteins by different host cell proteases

Dorothea, Bestle [Verfasser] / Friebertshäuser, Eva [Akademischer Betreuer]

2024

Author's details	Bestle Dorothea ; Betreuer: Eva Friebertshäuser
Keywords	Medizin, Gesundheit ; Medicine, Health
Subject code	sg610
Language	English
Publisher	Philipps-Universität Marburg
Publishing place	Marburg
Document type	Book ; Online ; Thesis
Database	Digital theses on the web

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Article ; Online: ACE2 acts as a novel regulator of TMPRSS2-catalyzed proteolytic activation of influenza A virus in airway cells.

Heindl, Miriam Ruth / Rupp, Anna-Lena / Schwerdtner, Marie / Bestle, Dorothea / Harbig, Anne / De Rocher, Amy / Schmacke, Luna C / Staker, Bart / Steinmetzer, Torsten / Stein, David A / Moulton, Hong M / Böttcher-Friebertshäuser, Eva

Journal of virology

2024 Volume 98, Issue 4, Page(s) e0010224

Abstract: The transmembrane serine protease 2 (TMPRSS2) activates the outer structural proteins of a number of respiratory viruses including influenza A virus (IAV), parainfluenza viruses, and various coronaviruses for membrane fusion. Previous studies showed that ...

Abstract	The transmembrane serine protease 2 (TMPRSS2) activates the outer structural proteins of a number of respiratory viruses including influenza A virus (IAV), parainfluenza viruses, and various coronaviruses for membrane fusion. Previous studies showed that TMPRSS2 interacts with the carboxypeptidase angiotensin-converting enzyme 2 (ACE2), a cell surface protein that serves as an entry receptor for some coronaviruses. Here, by using protease activity assays, we determine that ACE2 increases the enzymatic activity of TMPRSS2 in a non-catalytic manner. Furthermore, we demonstrate that ACE2 knockdown inhibits TMPRSS2-mediated cleavage of IAV hemagglutinin (HA) in Calu-3 human airway cells and suppresses virus titers 100- to 1.000-fold. Transient expression of ACE2 in ACE2-deficient cells increased TMPRSS2-mediated HA cleavage and IAV replication. ACE2 knockdown also reduced titers of MERS-CoV and prevented S cleavage by TMPRSS2 in Calu-3 cells. By contrast, proteolytic activation and multicycle replication of IAV with multibasic HA cleavage site typically cleaved by furin were not affected by ACE2 knockdown. Co-immunoprecipitation analysis revealed that ACE2-TMPRSS2 interaction requires the enzymatic activity of TMPRSS2 and the carboxypeptidase domain of ACE2. Together, our data identify ACE2 as a new co-factor or stabilizer of TMPRSS2 activity and as a novel host cell factor involved in proteolytic activation and spread of IAV in human airway cells. Furthermore, our data indicate that ACE2 is involved in the TMPRSS2-catalyzed activation of additional respiratory viruses including MERS-CoV.IMPORTANCEProteolytic cleavage of viral envelope proteins by host cell proteases is essential for the infectivity of many viruses and relevant proteases provide promising drug targets. The transmembrane serine protease 2 (TMPRSS2) has been identified as a major activating protease of several respiratory viruses, including influenza A virus. TMPRSS2 was previously shown to interact with angiotensin-converting enzyme 2 (ACE2). Here, we report the mechanistic details of this interaction. We demonstrate that ACE2 increases or stabilizes the enzymatic activity of TMPRSS2. Furthermore, we describe ACE2 involvement in TMPRSS2-catalyzed cleavage of the influenza A virus hemagglutinin and MERS-CoV spike protein in human airway cells. These findings expand our knowledge of the activation of respiratory viruses by TMPRSS2 and the host cell factors involved. In addition, our results could help to elucidate a physiological role for TMPRSS2.
MeSH term(s)	Humans ; Influenza A virus/physiology ; Angiotensin-Converting Enzyme 2 ; Hemagglutinins ; Proteolysis ; Catalysis ; Virus Internalization ; Serine Endopeptidases/genetics
Chemical Substances	Angiotensin-Converting Enzyme 2 (EC 3.4.17.23) ; Hemagglutinins ; TMPRSS2 protein, human (EC 3.4.21.-) ; Serine Endopeptidases (EC 3.4.21.-)
Language	English
Publishing date	2024-03-12
Publishing country	United States
Document type	Journal Article
ZDB-ID	80174-4
ISSN	1098-5514 ; 0022-538X
ISSN (online)	1098-5514
ISSN	0022-538X
DOI	10.1128/jvi.00102-24
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Article ; Online: Hemagglutinins of Avian Influenza Viruses Are Proteolytically Activated by TMPRSS2 in Human and Murine Airway Cells.

Bestle, Dorothea / Limburg, Hannah / Kruhl, Diana / Harbig, Anne / Stein, David A / Moulton, Hong / Matrosovich, Mikhail / Abdelwhab, Elsayed M / Stech, Jürgen / Böttcher-Friebertshäuser, Eva

Journal of virology

2021 Volume 95, Issue 20, Page(s) e0090621

Abstract: Cleavage of the influenza A virus (IAV) hemagglutinin (HA) by host proteases is indispensable for virus replication. Most IAVs possess a monobasic HA cleavage site cleaved by trypsin-like proteases. Previously, the transmembrane protease TMPRSS2 was ... ...

Abstract	Cleavage of the influenza A virus (IAV) hemagglutinin (HA) by host proteases is indispensable for virus replication. Most IAVs possess a monobasic HA cleavage site cleaved by trypsin-like proteases. Previously, the transmembrane protease TMPRSS2 was shown to be essential for proteolytic activation of IAV HA subtypes H1, H2, H7, and H10 in mice. In contrast, additional proteases are involved in activation of certain H3 IAVs, indicating that HAs with monobasic cleavage sites can differ in their sensitivity to host proteases. Here, we investigated the role of TMPRSS2 in proteolytic activation of avian HA subtypes H1 to H11 and H14 to H16 in human and mouse airway cell cultures. Using reassortant viruses carrying representative HAs, we analyzed HA cleavage and multicycle replication in (i) lung cells of TMPRSS2-deficient mice and (ii) Calu-3 cells and primary human bronchial cells subjected to morpholino oligomer-mediated knockdown of TMPRSS2 activity. TMPRSS2 was found to be crucial for activation of H1 to H11, H14, and H15 in airway cells of human and mouse. Only H9 with an R-S-S-R cleavage site and H16 were proteolytically activated in the absence of TMPRSS2 activity, albeit with reduced efficiency. Moreover, a TMPRSS2-orthologous protease from duck supported activation of H1 to H11, H15, and H16 in MDCK cells. Together, our data demonstrate that in human and murine respiratory cells, TMPRSS2 is the major activating protease of almost all IAV HA subtypes with monobasic cleavage sites. Furthermore, our results suggest that TMPRSS2 supports activation of IAV with a monobasic cleavage site in ducks.
MeSH term(s)	Animals ; Bronchi/cytology ; Cell Line ; Dogs ; Female ; HEK293 Cells ; Hemagglutinin Glycoproteins, Influenza Virus/genetics ; Hemagglutinin Glycoproteins, Influenza Virus/metabolism ; Hemagglutinins, Viral/genetics ; Hemagglutinins, Viral/metabolism ; Host-Pathogen Interactions ; Humans ; Influenza A Virus, H1N1 Subtype/physiology ; Influenza A Virus, H3N2 Subtype/physiology ; Influenza A virus/immunology ; Influenza A virus/metabolism ; Influenza A virus/pathogenicity ; Lung/virology ; Madin Darby Canine Kidney Cells ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Peptide Hydrolases/metabolism ; Proteolysis ; Respiratory Mucosa/metabolism ; Serine Endopeptidases/metabolism ; Serine Endopeptidases/physiology ; Virus Replication
Chemical Substances	Hemagglutinin Glycoproteins, Influenza Virus ; Hemagglutinins, Viral ; hemagglutinin, human influenza A virus ; trypsin-like serine protease ; Peptide Hydrolases (EC 3.4.-) ; Serine Endopeptidases (EC 3.4.21.-) ; TMPRSS2 protein, human (EC 3.4.21.-) ; TMPRSS2 protein, mouse (EC 3.4.21.-) ; virus activating protease (EC 3.4.21.-)
Language	English
Publishing date	2021-07-28
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80174-4
ISSN	1098-5514 ; 0022-538X
ISSN (online)	1098-5514
ISSN	0022-538X
DOI	10.1128/JVI.00906-21
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: TMPRSS2 Is the Major Activating Protease of Influenza A Virus in Primary Human Airway Cells and Influenza B Virus in Human Type II Pneumocytes.

Limburg, Hannah / Harbig, Anne / Bestle, Dorothea / Stein, David A / Moulton, Hong M / Jaeger, Julia / Janga, Harshavardhan / Hardes, Kornelia / Koepke, Janine / Schulte, Leon / Koczulla, Andreas Rembert / Schmeck, Bernd / Klenk, Hans-Dieter / Böttcher-Friebertshäuser, Eva

Journal of virology

2019 Volume 93, Issue 21

Abstract: Cleavage of influenza virus hemagglutinin (HA) by host cell proteases is essential for virus infectivity and spread. We previously ... ...

Abstract	Cleavage of influenza virus hemagglutinin (HA) by host cell proteases is essential for virus infectivity and spread. We previously demonstrated
MeSH term(s)	Animals ; Bronchi/cytology ; Cells, Cultured ; Epithelial Cells/virology ; Gene Knockdown Techniques ; Hemagglutinin Glycoproteins, Influenza Virus/metabolism ; Host-Pathogen Interactions ; Humans ; Influenza A virus/physiology ; Influenza B virus/physiology ; Influenza, Human/enzymology ; Influenza, Human/metabolism ; Influenza, Human/virology ; Mice ; Orthomyxoviridae Infections/enzymology ; Orthomyxoviridae Infections/metabolism ; Orthomyxoviridae Infections/virology ; Pulmonary Alveoli/cytology ; Serine Endopeptidases/genetics ; Serine Endopeptidases/metabolism ; Up-Regulation ; Virus Replication
Chemical Substances	Hemagglutinin Glycoproteins, Influenza Virus ; Serine Endopeptidases (EC 3.4.21.-) ; TMPRSS2 protein, human (EC 3.4.21.-)
Keywords	covid19
Language	English
Publishing date	2019-10-15
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80174-4
ISSN	1098-5514 ; 0022-538X
ISSN (online)	1098-5514
ISSN	0022-538X
DOI	10.1128/JVI.00649-19
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Jg. 1995 - 2021: Lesesall (1.OG)
ab Jg. 2022: Lesesaal (EG)

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Article ; Online: TMPRSS2 and furin are both essential for proteolytic activation of SARS-CoV-2 in human airway cells.

Bestle, Dorothea / Heindl, Miriam Ruth / Limburg, Hannah / Van Lam van, Thuy / Pilgram, Oliver / Moulton, Hong / Stein, David A / Hardes, Kornelia / Eickmann, Markus / Dolnik, Olga / Rohde, Cornelius / Klenk, Hans-Dieter / Garten, Wolfgang / Steinmetzer, Torsten / Böttcher-Friebertshäuser, Eva

Life science alliance

2020 Volume 3, Issue 9

Abstract: The novel emerged SARS-CoV-2 has rapidly spread around the world causing acute infection of the respiratory tract (COVID-19) that can result in severe disease and lethality. For SARS-CoV-2 to enter cells, its surface glycoprotein spike (S) must be ... ...

Abstract	The novel emerged SARS-CoV-2 has rapidly spread around the world causing acute infection of the respiratory tract (COVID-19) that can result in severe disease and lethality. For SARS-CoV-2 to enter cells, its surface glycoprotein spike (S) must be cleaved at two different sites by host cell proteases, which therefore represent potential drug targets. In the present study, we show that S can be cleaved by the proprotein convertase furin at the S1/S2 site and the transmembrane serine protease 2 (TMPRSS2) at the S2' site. We demonstrate that TMPRSS2 is essential for activation of SARS-CoV-2 S in Calu-3 human airway epithelial cells through antisense-mediated knockdown of TMPRSS2 expression. Furthermore, SARS-CoV-2 replication was also strongly inhibited by the synthetic furin inhibitor MI-1851 in human airway cells. In contrast, inhibition of endosomal cathepsins by E64d did not affect virus replication. Combining various TMPRSS2 inhibitors with furin inhibitor MI-1851 produced more potent antiviral activity against SARS-CoV-2 than an equimolar amount of any single serine protease inhibitor. Therefore, this approach has considerable therapeutic potential for treatment of COVID-19.
MeSH term(s)	Alveolar Epithelial Cells/cytology ; Alveolar Epithelial Cells/virology ; Animals ; Betacoronavirus/physiology ; Binding Sites ; Cell Line ; Chlorocebus aethiops ; Furin/genetics ; HEK293 Cells ; Humans ; Proteolysis ; SARS-CoV-2 ; Serine Endopeptidases/genetics ; Spike Glycoprotein, Coronavirus/chemistry ; Spike Glycoprotein, Coronavirus/metabolism ; Vero Cells ; Virus Internalization ; Virus Replication
Chemical Substances	Spike Glycoprotein, Coronavirus ; spike protein, SARS-CoV-2 ; Serine Endopeptidases (EC 3.4.21.-) ; TMPRSS2 protein, human (EC 3.4.21.-) ; FURIN protein, human (EC 3.4.21.75) ; Furin (EC 3.4.21.75)
Keywords	covid19
Language	English
Publishing date	2020-07-23
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2575-1077
ISSN (online)	2575-1077
DOI	10.26508/lsa.202000786
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Hemagglutinins of avian influenza viruses are proteolytically activated by TMPRSS2 in human and murine airway cells

Bestle, Dorothea / Limburg, Hannah / Kruhl, Diana / Harbig, Anne / Stein, David A. / Moulton, Hong / Matrosovich, Mikhail / Abd el-Whab, El-Sayed Mohammed / Stech, Jürgen / Böttcher-Friebertshäuser, Eva

2021

Abstract	Cleavage of the influenza A virus (IAV) hemagglutinin (HA) by host proteases is indispensable for virus replication. Most IAVs possess a monobasic HA cleavage site cleaved by trypsin-like proteases. Previously, the transmembrane protease TMPRSS2 was shown to be essential for proteolytic activation of IAV HA subtypes H1, H2, H7 and H10 in mice. In contrast, additional proteases are involved in activation of certain H3 IAVs, indicating that HAs with monobasic cleavage site can differ in their sensitivity to host proteases. Here, we investigated the role of TMPRSS2 in proteolytic activation of avian HA subtypes H1 to H11 and H14 to H16 in human and mouse airway cell cultures. Using reassortant viruses carrying representative HAs, we analysed HA cleavage and multicycle replication in (i) lung cells of TMPRSS2-deficient mice and (ii) Calu-3 cells and primary human bronchial cells subjected to morpholino oligomer-mediated knockdown of TMPRSS2 activity. TMPRSS2 was found to be crucial for activation of H1 to H11, H14 and H15 in airway cells of human and mouse. Only H9 with an R-S-S-R cleavage site and H16 were proteolytically activated in the absence of TMPRSS2 activity, albeit with reduced efficiency. Moreover, a TMPRSS2-orthologous protease from duck supported activation of H1 to H11, H15 and H16 in MDCK cells. Together, our data demonstrate that in human and murine respiratory cells, TMPRSS2 is the major activating protease of almost all IAV HA subtypes with monobasic cleavage site. Furthermore, our results suggest that TMPRSS2 supports activation of IAV with monobasic cleavage site in ducks. Importance Human infections with avian influenza A viruses upon exposure to infected birds are frequently reported and have received attention as a potential pandemic threat. Cleavage of the envelope glycoprotein hemagglutinin (HA) by host proteases is a prerequisite for membrane fusion and essential for virus infectivity. In this study, we identify the transmembrane protease TMPRSS2 as the major activating protease of avian ...
Keywords	Text ; ddc:570 ; influenza virus -- TMPRSS2 -- hemagglutinin -- monobasic cleavage site -- virus activating protease -- primary airway cells -- avian influenza -- morpholino oligomers
Subject code	570
Language	English
Publishing date	2021-07-28
Publishing country	de
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: TMPRSS2 and furin are both essential for proteolytic activation of SARS-CoV-2 in human airway cells

Abstract	The novel emerged SARS-CoV-2 has rapidly spread around the world causing acute infection of the respiratory tract (COVID-19) that can result in severe disease and lethality. For SARS-CoV-2 to enter cells, its surface glycoprotein spike (S) must be cleaved at two different sites by host cell proteases, which therefore represent potential drug targets. In the present study, we show that S can be cleaved by the proprotein convertase furin at the S1/S2 site and the transmembrane serine protease 2 (TMPRSS2) at the S2' site. We demonstrate that TMPRSS2 is essential for activation of SARS-CoV-2 S in Calu-3 human airway epithelial cells through antisense-mediated knockdown of TMPRSS2 expression. Furthermore, SARS-CoV-2 replication was also strongly inhibited by the synthetic furin inhibitor MI-1851 in human airway cells. In contrast, inhibition of endosomal cathepsins by E64d did not affect virus replication. Combining various TMPRSS2 inhibitors with furin inhibitor MI-1851 produced more potent antiviral activity against SARS-CoV-2 than an equimolar amount of any single serine protease inhibitor. Therefore, this approach has considerable therapeutic potential for treatment of COVID-19.
Keywords	covid19
Publisher	WHO
Document type	Article
Note	WHO #Covidence: #675904
Database	COVID19

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Article ; Online: TMPRSS2 and furin are both essential for proteolytic activation and spread of SARS-CoV-2 in human airway epithelial cells and provide promising drug targets

Bestle, Dorothea / Heindl, Miriam Ruth / Limburg, Hannah / van, Thuy Van Lam / Pilgram, Oliver / Moulton, Hong / Stein, David A. / Hardes, Kornelia / Eickmann, Markus / Dolnik, Olga / Rohde, Cornelius / Becker, Stephan / Klenk, Hans-Dieter / Garten, Wolfgang / Steinmetzer, Torsten / Böttcher-Friebertshäuser, Eva

bioRxiv

Abstract: In December 2019, a novel coronavirus named SARS-CoV-2 first reported in Wuhan, China, emerged and rapidly spread to numerous other countries globally, causing the current pandemic. SARS-CoV-2 causes acute infection of the respiratory tract (COVID-19) ... ...

Abstract	In December 2019, a novel coronavirus named SARS-CoV-2 first reported in Wuhan, China, emerged and rapidly spread to numerous other countries globally, causing the current pandemic. SARS-CoV-2 causes acute infection of the respiratory tract (COVID-19) that can result in severe disease and lethality. Currently, there is no approved antiviral drug for treating COVID-19 patients and there is an urgent need for specific antiviral therapies and vaccines. In order for SARS-CoV-2 to enter cells, its surface glycoprotein spike (S) must be cleaved at two different sites by host cell proteases, which therefore represent potential drug targets. In the present study we investigated which host cell proteases activate the SARS-CoV-2 S protein in Calu-3 human airway epithelial cells. We show that S can be cleaved by both the proprotein convertase furin at the S1/S2 site and the transmembrane serine protease 2 (TMPRSS2) at the S2’ site. We demonstrate that TMPRSS2 is essential for activation of SARS-CoV-2 S in Calu-3 cells through antisense-mediated knockdown of TMPRSS2 expression. Further, we show that SARS-CoV-2 replication can be efficiently inhibited by two synthetic inhibitors of TMPRSS2 and also by the broad range serine protease inhibitor aprotinin. Additionally, SARS-CoV-2 replication was also strongly inhibited by the synthetic furin inhibitor MI-1851. Combining various TMPRSS2 inhibitors with MI-1851 produced more potent antiviral activity against SARS-CoV-2 than an equimolar amount of any single serine protease inhibitor. In contrast, inhibition of endosomal cathepsins by E64d did not affect virus replication. Our data demonstrate that both TMPRSS2 and furin are essential for SARS-CoV-2 activation in human airway cells and are promising drug targets for the treatment of COVID-19 either by targeting one of these proteases alone or by a combination of furin and TMPRSS2 inhibitors. Therefore, this approach has a high therapeutic potential for treatment of COVID-19.
Keywords	covid19
Publisher	BioRxiv; WHO
Document type	Article ; Online
DOI	10.1101/2020.04.15.042085
Database	COVID19

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Article ; Online: TMPRSS2 and furin are both essential for proteolytic activation and spread of SARS-CoV-2 in human airway epithelial cells and provide promising drug targets

bioRxiv

Abstract	In December 2019, a novel coronavirus named SARS-CoV-2 first reported in Wuhan, China, emerged and rapidly spread to numerous other countries globally, causing the current pandemic. SARS-CoV-2 causes acute infection of the respiratory tract (COVID-19) that can result in severe disease and lethality. Currently, there is no approved antiviral drug for treating COVID-19 patients and there is an urgent need for specific antiviral therapies and vaccines. In order for SARS-CoV-2 to enter cells, its surface glycoprotein spike (S) must be cleaved at two different sites by host cell proteases, which therefore represent potential drug targets. In the present study we investigated which host cell proteases activate the SARS-CoV-2 S protein in Calu-3 human airway epithelial cells. We show that S can be cleaved by both the proprotein convertase furin at the S1/S2 site and the transmembrane serine protease 2 (TMPRSS2) at the S2 site. We demonstrate that TMPRSS2 is essential for activation of SARS-CoV-2 S in Calu-3 cells through antisense-mediated knockdown of TMPRSS2 expression. Further, we show that SARS-CoV-2 replication can be efficiently inhibited by two synthetic inhibitors of TMPRSS2 and also by the broad range serine protease inhibitor aprotinin. Additionally, SARS-CoV-2 replication was also strongly inhibited by the synthetic furin inhibitor MI-1851. Combining various TMPRSS2 inhibitors with MI-1851 produced more potent antiviral activity against SARS-CoV-2 than an equimolar amount of any single serine protease inhibitor. In contrast, inhibition of endosomal cathepsins by E64d did not affect virus replication. Our data demonstrate that both TMPRSS2 and furin are essential for SARS-CoV-2 activation in human airway cells and are promising drug targets for the treatment of COVID-19 either by targeting one of these proteases alone or by a combination of furin and TMPRSS2 inhibitors. Therefore, this approach has a high therapeutic potential for treatment of COVID-19.
Keywords	covid19
Language	English
Publishing date	2020-04-15
Publisher	Cold Spring Harbor Laboratory
Document type	Article ; Online
DOI	10.1101/2020.04.15.042085
Database	COVID19

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