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Book ; Online ; Thesis: Characterization of host cell factors used by emerging coronaviruses for entry into target cells

2020

Author's details	Hannah Kleine-Weber
Keywords	Biowissenschaften, Biologie ; Life Science, Biology
Subject code	sg570
Language	German
Publisher	Niedersächsische Staats- und Universitätsbibliothek Göttingen
Publishing place	Göttingen
Document type	Book ; Online ; Thesis
Database	Digital theses on the web

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Article ; Online: Development and Evaluation of Peptidomimetic Compounds against SARS-CoV-2 Spike Protein: An in silico and in vitro Study.

Zarei, Omid / Kleine-Weber, Hannah / Hoffmann, Markus / Hamzeh-Mivehroud, Maryam

Molecular informatics

2022 Volume 41, Issue 7, Page(s) e2100231

Abstract: Background: Coronavirus disease 2019 (COVID-19) as global pandemic disease has been adversely affecting public health and social life with considerable loss of human life worldwide. Therefore, there is an urgent need for developing novel therapeutics to ...

Abstract	Background: Coronavirus disease 2019 (COVID-19) as global pandemic disease has been adversely affecting public health and social life with considerable loss of human life worldwide. Therefore, there is an urgent need for developing novel therapeutics to combat COVID-19. The causative agent of COVID-19 is SARS-CoV-2 which targets human angiotensin converting enzyme 2 (ACE2) as cellular receptor via its spike (S) protein. In this context, interfering with the binding of SARS-CoV-2 S protein to target molecules could provide a promising strategy to find novel therapeutic agents against SARS-CoV-2. The purpose of the current study was to identify potential peptidomimetics against S protein with a combination of structure-based virtual screening methods and in vitro assays. Methods: The candidates were inspected in terms of ADME properties, drug-likeness, as well as toxicity profiles. Additionally, molecular docking and dynamics simulations were performed to predict binding of the studied ligands to spike protein. Results: Biological evaluation of the compounds revealed that PM2 molecule exhibits some antiviral activity. Conclusion: In summary, this study highlights the importance of combining in silico and in vitro techniques in order to identify antiviral compound to tackle COVID-19 and presents a new scaffold that may be structurally optimized for improved antiviral activity.
MeSH term(s)	Antiviral Agents/chemistry ; Molecular Docking Simulation ; Peptidomimetics/pharmacology ; SARS-CoV-2/drug effects ; Spike Glycoprotein, Coronavirus/antagonists & inhibitors ; Spike Glycoprotein, Coronavirus/chemistry
Chemical Substances	Antiviral Agents ; Peptidomimetics ; Spike Glycoprotein, Coronavirus ; spike protein, SARS-CoV-2
Language	English
Publishing date	2022-02-01
Publishing country	Germany
Document type	Journal Article
ZDB-ID	2537668-8
ISSN	1868-1751 ; 1868-1743
ISSN (online)	1868-1751
ISSN	1868-1743
DOI	10.1002/minf.202100231
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: A Multibasic Cleavage Site in the Spike Protein of SARS-CoV-2 Is Essential for Infection of Human Lung Cells.

Hoffmann, Markus / Kleine-Weber, Hannah / Pöhlmann, Stefan

Molecular cell

2020 Volume 78, Issue 4, Page(s) 779–784.e5

Abstract: The pandemic coronavirus SARS-CoV-2 threatens public health worldwide. The viral spike protein mediates SARS-CoV-2 entry into host cells and harbors a S1/S2 cleavage site containing multiple arginine residues (multibasic) not found in closely related ... ...

Abstract	The pandemic coronavirus SARS-CoV-2 threatens public health worldwide. The viral spike protein mediates SARS-CoV-2 entry into host cells and harbors a S1/S2 cleavage site containing multiple arginine residues (multibasic) not found in closely related animal coronaviruses. However, the role of this multibasic cleavage site in SARS-CoV-2 infection is unknown. Here, we report that the cellular protease furin cleaves the spike protein at the S1/S2 site and that cleavage is essential for S-protein-mediated cell-cell fusion and entry into human lung cells. Moreover, optimizing the S1/S2 site increased cell-cell, but not virus-cell, fusion, suggesting that the corresponding viral variants might exhibit increased cell-cell spread and potentially altered virulence. Our results suggest that acquisition of a S1/S2 multibasic cleavage site was essential for SARS-CoV-2 infection of humans and identify furin as a potential target for therapeutic intervention.
MeSH term(s)	Animals ; Betacoronavirus/chemistry ; Betacoronavirus/physiology ; COVID-19 ; Cell Line ; Chlorocebus aethiops ; Coronavirus Infections/virology ; Furin/chemistry ; Furin/genetics ; Furin/metabolism ; Humans ; Lung/metabolism ; Lung/virology ; Pandemics ; Pneumonia, Viral/virology ; SARS-CoV-2 ; Serine Endopeptidases/metabolism ; Spike Glycoprotein, Coronavirus/chemistry ; Spike Glycoprotein, Coronavirus/genetics ; Spike Glycoprotein, Coronavirus/metabolism ; Vero Cells ; Virus Attachment
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	2020-05-01
Publishing country	United States
Document type	Journal Article
ZDB-ID	1415236-8
ISSN	1097-4164 ; 1097-2765
ISSN (online)	1097-4164
ISSN	1097-2765
DOI	10.1016/j.molcel.2020.04.022
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Article ; Online: Spike proteins of novel MERS-coronavirus isolates from North- and West-African dromedary camels mediate robust viral entry into human target cells.

Kleine-Weber, Hannah / Pöhlmann, Stefan / Hoffmann, Markus

Virology

2019 Volume 535, Page(s) 261–265

Abstract: The highly pathogenic Middle East respiratory syndrome (MERS)-related coronavirus (CoV) is transmitted from dromedary camels, the natural reservoir, to humans. For at present unclear reasons, MERS cases have so far only been observed in the Arabian ... ...

Abstract	The highly pathogenic Middle East respiratory syndrome (MERS)-related coronavirus (CoV) is transmitted from dromedary camels, the natural reservoir, to humans. For at present unclear reasons, MERS cases have so far only been observed in the Arabian Peninsula, although MERS-CoV also circulates in African dromedary camels. A recent study showed that MERS-CoV found in North/West- (Morocco) and West-African (Burkina Faso and Nigeria) dromedary camels are genetically distinct from Arabian viruses and have reduced replicative capacity in human cells, potentially due to amino acid changes in one or more viral proteins. Here, we show that the spike (S) proteins of the prototypic Arabian MERS-CoV strain, human betacoronavirus 2c EMC/2012, and the above stated African MERS-CoV variants do not appreciably differ in expression, DPP4 binding and ability to drive entry into target cells. Thus, virus-host-interactions at the entry stage may not limit spread of North- and West-African MERS-CoV in human cells.
MeSH term(s)	Africa, Northern ; Africa, Western ; Amino Acid Substitution ; Animals ; Camelus ; Cell Line ; Humans ; Middle East Respiratory Syndrome Coronavirus/genetics ; Middle East Respiratory Syndrome Coronavirus/isolation & purification ; Middle East Respiratory Syndrome Coronavirus/physiology ; Spike Glycoprotein, Coronavirus/genetics ; Spike Glycoprotein, Coronavirus/metabolism ; Virus Internalization
Chemical Substances	Spike Glycoprotein, Coronavirus
Keywords	covid19
Language	English
Publishing date	2019-07-19
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	200425-2
ISSN	1096-0341 ; 0042-6822
ISSN (online)	1096-0341
ISSN	0042-6822
DOI	10.1016/j.virol.2019.07.016
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Article ; Online: A Multibasic Cleavage Site in the Spike Protein of SARS-CoV-2 Is Essential for Infection of Human Lung Cells

Hoffmann, Markus / Kleine-Weber, Hannah / Pöhlmann, Stefan

Molecular Cell

2020 Volume 78, Issue 4, Page(s) 779–784.e5

Keywords	Cell Biology ; Molecular Biology ; covid19
Language	English
Publisher	Elsevier BV
Publishing country	us
Document type	Article ; Online
ZDB-ID	1415236-8
ISSN	1097-4164 ; 1097-2765
ISSN (online)	1097-4164
ISSN	1097-2765
DOI	10.1016/j.molcel.2020.04.022
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: A Multibasic Cleavage Site in the Spike Protein of SARS-CoV-2 Is Essential for Infection of Human Lung Cells

Hoffmann, Markus / Kleine-Weber, Hannah / Pöhlmann, Stefan

Mol Cell

Abstract	The pandemic coronavirus SARS-CoV-2 threatens public health worldwide. The viral spike protein mediates SARS-CoV-2 entry into host cells and harbors a S1/S2 cleavage site containing multiple arginine residues (multibasic) not found in closely related animal coronaviruses. However, the role of this multibasic cleavage site in SARS-CoV-2 infection is unknown. Here, we report that the cellular protease furin cleaves the spike protein at the S1/S2 site and that cleavage is essential for S-protein-mediated cell-cell fusion and entry into human lung cells. Moreover, optimizing the S1/S2 site increased cell-cell, but not virus-cell, fusion, suggesting that the corresponding viral variants might exhibit increased cell-cell spread and potentially altered virulence. Our results suggest that acquisition of a S1/S2 multibasic cleavage site was essential for SARS-CoV-2 infection of humans and identify furin as a potential target for therapeutic intervention.
Keywords	covid19
Publisher	WHO
Document type	Article
Note	WHO #Covidence: #88548
Database	COVID19

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Article ; Online: Nafamostat Mesylate Blocks Activation of SARS-CoV-2: New Treatment Option for COVID-19.

Hoffmann, Markus / Schroeder, Simon / Kleine-Weber, Hannah / Müller, Marcel A / Drosten, Christian / Pöhlmann, Stefan

Antimicrobial agents and chemotherapy

2020 Volume 64, Issue 6

MeSH term(s)	Betacoronavirus ; COVID-19 ; Coronavirus Infections ; Guanidines ; Pandemics ; Peptidyl-Dipeptidase A ; Pneumonia, Viral ; Protease Inhibitors ; SARS Virus ; SARS-CoV-2 ; Virus Internalization
Chemical Substances	Guanidines ; Protease Inhibitors ; Peptidyl-Dipeptidase A (EC 3.4.15.1) ; nafamostat (Y25LQ0H97D)
Keywords	covid19
Language	English
Publishing date	2020-05-21
Publishing country	United States
Document type	Letter ; Comment
ZDB-ID	217602-6
ISSN	1098-6596 ; 0066-4804
ISSN (online)	1098-6596
ISSN	0066-4804
DOI	10.1128/AAC.00754-20
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Article ; Online: Functional analysis of potential cleavage sites in the MERS-coronavirus spike protein.

Kleine-Weber, Hannah / Elzayat, Mahmoud Tarek / Hoffmann, Markus / Pöhlmann, Stefan

Scientific reports

2018 Volume 8, Issue 1, Page(s) 16597

Abstract: The Middle East respiratory syndrome-related coronavirus (MERS-CoV) can cause severe disease and has pandemic potential. Therefore, development of antiviral strategies is an important task. The activation of the viral spike protein (S) by host cell ... ...

Abstract	The Middle East respiratory syndrome-related coronavirus (MERS-CoV) can cause severe disease and has pandemic potential. Therefore, development of antiviral strategies is an important task. The activation of the viral spike protein (S) by host cell proteases is essential for viral infectivity and the responsible enzymes are potential therapeutic targets. The cellular proteases furin, cathepsin L and TMPRSS2 can activate MERS-S and may cleave the S protein at two distinct sites, termed S1/S2 and S2'. Moreover, a potential cathepsin L cleavage site in MERS-S has been reported. However, the relative importance of these sites for MERS-S activation is incompletely understood. Here, we used mutagenic analysis and MERS-S-bearing vectors to study the contribution of specific cleavage sites to S protein-driven entry. We found that an intact S1/S2 site was only required for efficient entry into cells expressing endogenous TMPRSS2. In keeping with a previous study, pre-cleavage at the S1/S2 motif (RSVR) was important although not essential for subsequent MERS-S activation by TMPRSS2, and indirect evidence was obtained that this motif is processed by a protease depending on an intact RXXR motif, most likely furin. In contrast, the S2' site (RSAR) was required for robust viral entry into all cell lines tested and the integrity of one of the two arginines was sufficient for efficient entry. These findings suggest that cleavage at S2' is carried out by proteases recognizing a single arginine, most likely TMPRSS2 and cathepsin L. Finally, mutation of the proposed cathepsin L site did not impact viral entry and double mutation of S1/S2 and S2' site was compatible with cathepsin L- but not TMPRSS2-dependent host cell entry, indicating that cathepsin L can process the S protein at auxiliary sites. Collectively, our results indicate a rigid sequence requirement for S protein activation by TMPRSS2 but not cathepsin L.
MeSH term(s)	Animals ; Cathepsin L/genetics ; Cathepsin L/metabolism ; Chlorocebus aethiops ; Coronavirus Infections/virology ; Furin/genetics ; Furin/metabolism ; Humans ; Middle East Respiratory Syndrome Coronavirus/physiology ; Mutation ; Proteolysis ; Serine Endopeptidases/genetics ; Serine Endopeptidases/metabolism ; Spike Glycoprotein, Coronavirus/genetics ; Spike Glycoprotein, Coronavirus/metabolism ; Vero Cells ; Virus Internalization
Chemical Substances	Spike Glycoprotein, Coronavirus ; 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) ; Cathepsin L (EC 3.4.22.15)
Keywords	covid19
Language	English
Publishing date	2018-11-09
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-018-34859-w
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: SARS-CoV-2 and SARS-CoV Spike-Mediated Cell-Cell Fusion Differ in Their Requirements for Receptor Expression and Proteolytic Activation.

Hörnich, Bojan F / Großkopf, Anna K / Schlagowski, Sarah / Tenbusch, Matthias / Kleine-Weber, Hannah / Neipel, Frank / Stahl-Hennig, Christiane / Hahn, Alexander S

Journal of virology

2021 Volume 95, Issue 9

Abstract: Severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) infects cells through interaction of its spike protein (SARS2-S) with angiotensin-converting enzyme 2 (ACE2) and activation by proteases, in particular transmembrane protease serine 2 ( ... ...

Abstract	Severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) infects cells through interaction of its spike protein (SARS2-S) with angiotensin-converting enzyme 2 (ACE2) and activation by proteases, in particular transmembrane protease serine 2 (TMPRSS2). Viruses can also spread through fusion of infected with uninfected cells. We compared the requirements of ACE2 expression, proteolytic activation, and sensitivity to inhibitors for SARS2-S-mediated and SARS-CoV-S (SARS1-S)-mediated cell-cell fusion. SARS2-S-driven fusion was moderately increased by TMPRSS2 and strongly by ACE2, while SARS1-S-driven fusion was strongly increased by TMPRSS2 and less so by ACE2 expression. In contrast to that of SARS1-S, SARS2-S-mediated cell-cell fusion was efficiently activated by batimastat-sensitive metalloproteases. Mutation of the S1/S2 proteolytic cleavage site reduced effector cell-target cell fusion when ACE2 or TMPRSS2 was limiting and rendered SARS2-S-driven cell-cell fusion more dependent on TMPRSS2. When both ACE2 and TMPRSS2 were abundant, initial target cell-effector cell fusion was unaltered compared to that of wild-type (wt) SARS2-S, but syncytia remained smaller. Mutation of the S2 cleavage (S2') site specifically abrogated activation by TMPRSS2 for both cell-cell fusion and SARS2-S-driven pseudoparticle entry but still allowed for activation by metalloproteases for cell-cell fusion and by cathepsins for particle entry. Finally, we found that the TMPRSS2 inhibitor bromhexine, unlike the inhibitor camostat, was unable to reduce TMPRSS2-activated cell-cell fusion by SARS1-S and SARS2-S. Paradoxically, bromhexine enhanced cell-cell fusion in the presence of TMPRSS2, while its metabolite ambroxol exhibited inhibitory activity under some conditions. On Calu-3 lung cells, ambroxol weakly inhibited SARS2-S-driven lentiviral pseudoparticle entry, and both substances exhibited a dose-dependent trend toward weak inhibition of authentic SARS-CoV-2.
MeSH term(s)	Ambroxol/pharmacology ; Amino Acid Substitution ; Angiotensin-Converting Enzyme 2/genetics ; Angiotensin-Converting Enzyme 2/metabolism ; Bromhexine/pharmacology ; COVID-19/genetics ; COVID-19/metabolism ; Cell Line ; Humans ; Mutation, Missense ; Proteolysis/drug effects ; Severe acute respiratory syndrome-related coronavirus/genetics ; Severe acute respiratory syndrome-related coronavirus/metabolism ; SARS-CoV-2/genetics ; SARS-CoV-2/metabolism ; Serine Endopeptidases/genetics ; Serine Endopeptidases/metabolism ; Severe Acute Respiratory Syndrome/genetics ; Severe Acute Respiratory Syndrome/metabolism ; Spike Glycoprotein, Coronavirus/genetics ; Spike Glycoprotein, Coronavirus/metabolism ; Virus Internalization
Chemical Substances	Spike Glycoprotein, Coronavirus ; spike protein, SARS-CoV-2 ; Ambroxol (200168S0CL) ; ACE2 protein, human (EC 3.4.17.23) ; Angiotensin-Converting Enzyme 2 (EC 3.4.17.23) ; Serine Endopeptidases (EC 3.4.21.-) ; TMPRSS2 protein, human (EC 3.4.21.-) ; Bromhexine (Q1J152VB1P)
Language	English
Publishing date	2021-04-12
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.00002-21
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Article: Nafamostat Mesylate Blocks Activation of SARS-CoV-2: New Treatment Option for COVID-19

Hoffmann, Markus / Schroeder, Simon / Kleine-Weber, Hannah / Müller, Marcel A / Drosten, Christian / Pöhlmann, Stefan

Keywords	covid19
Publisher	WHO
Document type	Article
Note	WHO #Covidence: #88701
Database	COVID19

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