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Vaccines and Antiviral Agents

Labyrinthopeptins Exert Broad-Spectrum Antiviral Activity through Lipid-Binding-Mediated Virolysis

Hans Prochnow, Katharina Rox, N. V. Suryanarayana Birudukota, Loreen Weichert, Sven-Kevin Hotop, Philipp Klahn, Kathrin Mohr, Sergej Franz, Dominic H. Banda, Sebastian Blockus, Janine Schreiber, Sibylle Haid, Merel Oeyen, Javier P. Martinez, Roderich D. Süssmuth, Joachim Wink, Andreas Meyerhans, Christine Goffinet, Martin Messerle, Thomas F. Schulz, Andrea Kröger, Dominique Schols, Thomas Pietschmann, Mark Brönstrup
Mark T. Heise, Editor
Hans Prochnow
aDepartment of Chemical Biology, Helmholtz Centre for Infection Research, Braunschweig, Germany
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Katharina Rox
aDepartment of Chemical Biology, Helmholtz Centre for Infection Research, Braunschweig, Germany
bGerman Centre for Infection Research (DZIF), Partner Site Hannover-Braunschweig, Hannover, Germany
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N. V. Suryanarayana Birudukota
aDepartment of Chemical Biology, Helmholtz Centre for Infection Research, Braunschweig, Germany
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Loreen Weichert
cInnate Immunity and Infection, Helmholtz Centre for Infection Research, Braunschweig, Germany
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Sven-Kevin Hotop
aDepartment of Chemical Biology, Helmholtz Centre for Infection Research, Braunschweig, Germany
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Philipp Klahn
aDepartment of Chemical Biology, Helmholtz Centre for Infection Research, Braunschweig, Germany
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Kathrin Mohr
dDepartment of Microbial Drugs, Helmholtz Centre for Infection Research, Braunschweig, Germany
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Sergej Franz
eInstitute of Experimental Virology, TWINCORE, Hannover, Germany
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Dominic H. Banda
eInstitute of Experimental Virology, TWINCORE, Hannover, Germany
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Sebastian Blockus
eInstitute of Experimental Virology, TWINCORE, Hannover, Germany
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Janine Schreiber
aDepartment of Chemical Biology, Helmholtz Centre for Infection Research, Braunschweig, Germany
bGerman Centre for Infection Research (DZIF), Partner Site Hannover-Braunschweig, Hannover, Germany
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Sibylle Haid
eInstitute of Experimental Virology, TWINCORE, Hannover, Germany
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Merel Oeyen
fRega Institute for Medical Research, Department of Microbiology and Immunology, University of Leuven, Leuven, Belgium
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Javier P. Martinez
gInfection Biology Laboratory, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain
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Roderich D. Süssmuth
hInstitut für Chemie, Technische Universität Berlin, Berlin, Germany
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Joachim Wink
iMicrobial Strain Collection, Helmholtz Centre for Infection Research, Braunschweig, Germany
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Andreas Meyerhans
gInfection Biology Laboratory, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain
jICREA, Barcelona, Spain
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Christine Goffinet
eInstitute of Experimental Virology, TWINCORE, Hannover, Germany
kInstitute of Virology, Campus Charité Mitte, Charité-Universitätsmedizin Berlin, Berlin, Germany
lBerlin Institute of Health, Berlin, Germany
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Martin Messerle
mInstitute of Virology, Hannover Medical School, Hannover, Germany
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Thomas F. Schulz
bGerman Centre for Infection Research (DZIF), Partner Site Hannover-Braunschweig, Hannover, Germany
mInstitute of Virology, Hannover Medical School, Hannover, Germany
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Andrea Kröger
cInnate Immunity and Infection, Helmholtz Centre for Infection Research, Braunschweig, Germany
nInstitute for Medical Microbiology, Otto von Guericke University, Magdeburg, Germany
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Dominique Schols
fRega Institute for Medical Research, Department of Microbiology and Immunology, University of Leuven, Leuven, Belgium
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Thomas Pietschmann
bGerman Centre for Infection Research (DZIF), Partner Site Hannover-Braunschweig, Hannover, Germany
eInstitute of Experimental Virology, TWINCORE, Hannover, Germany
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Mark Brönstrup
aDepartment of Chemical Biology, Helmholtz Centre for Infection Research, Braunschweig, Germany
bGerman Centre for Infection Research (DZIF), Partner Site Hannover-Braunschweig, Hannover, Germany
oBiomolecular Drug Research Center (BMWZ), Leibniz University Hannover, Hannover, Germany
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Mark T. Heise
University of North Carolina at Chapel Hill
Roles: Editor
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DOI: 10.1128/JVI.01471-19
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ABSTRACT

To counteract the serious health threat posed by known and novel viral pathogens, drugs that target a variety of viruses through a common mechanism have attracted recent attention due to their potential in treating (re)emerging infections, for which direct-acting antivirals are not available. We found that labyrinthopeptins A1 and A2, the prototype congeners of carbacyclic lanthipeptides, inhibit the proliferation of diverse enveloped viruses, including dengue virus, Zika virus, West Nile virus, hepatitis C virus, chikungunya virus, Kaposi’s sarcoma-associated herpesvirus, cytomegalovirus, and herpes simplex virus, in the low micromolar to nanomolar range. Mechanistic studies on viral particles revealed that labyrinthopeptins induce a virolytic effect through binding to the viral membrane lipid phosphatidylethanolamine (PE). These effects are enhanced by a combined equimolar application of both labyrinthopeptins, and a clear synergism was observed across a concentration range corresponding to 10% to 90% inhibitory concentrations of the compounds. Time-resolved experiments with large unilamellar vesicles (LUVs) reveal that membrane lipid raft compositions (phosphatidylcholine [PC]/PE/cholesterol/sphingomyelin at 17:10:33:40) are particularly sensitive to labyrinthopeptins in comparison to PC/PE (90:10) LUVs, even though the overall PE amount remains constant. Labyrinthopeptins exhibited low cytotoxicity and had favorable pharmacokinetic properties in mice (half-life [t1/2] = 10.0 h), which designates them promising antiviral compounds acting by an unusual viral lipid targeting mechanism.

IMPORTANCE For many viral infections, current treatment options are insufficient. Because the development of each antiviral drug is time-consuming and expensive, the prospect of finding broad-spectrum antivirals that can fight multiple, diverse viruses—well-known viruses as well as (re)emerging species—has gained attention, especially for the treatment of viral coinfections. While most known broad-spectrum agents address processes in the host cell, we found that targeting lipids of the free virus outside the host cell with the natural products labyrinthopeptin A1 and A2 is a viable strategy to inhibit the proliferation of a broad range of viruses from different families, including chikungunya virus, dengue virus, Zika virus, Kaposi’s sarcoma-associated herpesvirus, and cytomegalovirus. Labyrinthopeptins bind to viral phosphatidylethanolamine and induce virolysis without exerting cytotoxicity on host cells. This represents a novel and unusual mechanism to tackle medically relevant viral infections.

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Labyrinthopeptins Exert Broad-Spectrum Antiviral Activity through Lipid-Binding-Mediated Virolysis
Hans Prochnow, Katharina Rox, N. V. Suryanarayana Birudukota, Loreen Weichert, Sven-Kevin Hotop, Philipp Klahn, Kathrin Mohr, Sergej Franz, Dominic H. Banda, Sebastian Blockus, Janine Schreiber, Sibylle Haid, Merel Oeyen, Javier P. Martinez, Roderich D. Süssmuth, Joachim Wink, Andreas Meyerhans, Christine Goffinet, Martin Messerle, Thomas F. Schulz, Andrea Kröger, Dominique Schols, Thomas Pietschmann, Mark Brönstrup
Journal of Virology Jan 2020, 94 (2) e01471-19; DOI: 10.1128/JVI.01471-19

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Labyrinthopeptins Exert Broad-Spectrum Antiviral Activity through Lipid-Binding-Mediated Virolysis
Hans Prochnow, Katharina Rox, N. V. Suryanarayana Birudukota, Loreen Weichert, Sven-Kevin Hotop, Philipp Klahn, Kathrin Mohr, Sergej Franz, Dominic H. Banda, Sebastian Blockus, Janine Schreiber, Sibylle Haid, Merel Oeyen, Javier P. Martinez, Roderich D. Süssmuth, Joachim Wink, Andreas Meyerhans, Christine Goffinet, Martin Messerle, Thomas F. Schulz, Andrea Kröger, Dominique Schols, Thomas Pietschmann, Mark Brönstrup
Journal of Virology Jan 2020, 94 (2) e01471-19; DOI: 10.1128/JVI.01471-19
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KEYWORDS

lanthipeptides
antivirals
drug discovery
mechanism of action
phosphatidylethanolamine
lipids
drug synergism
dengue virus
DENV
Zika virus
ZIKV

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