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Luminescent reporter cells enable the identification of broad-spectrum antivirals against emerging viruses

Löw, Karin (författare)
Department of Biochemistry & Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine Hannover, Hannover, Germany; Institute of Microbiology, University Hospital Center and University of Lausanne, Lausanne, Switzerland
Möller, Rebecca (författare)
Department of Biochemistry & Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine Hannover, Hannover, Germany
Stegmann, Cora (författare)
Department of Biochemistry & Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine Hannover, Hannover, Germany
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Becker, Miriam (författare)
Department of Biochemistry & Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine Hannover, Hannover, Germany
Rehburg, Laura (författare)
Department of Biochemistry & Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine Hannover, Hannover, Germany
Obernolte, Helena (författare)
Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM), Hannover, Germany; Fraunhofer International Consortium for Anti-Infective Research (iCAIR), Hannover, Germany; Fraunhofer Cluster of Excellence Immune-Mediated Diseases, (CIMD), Hannover, Germany; Member of the German Center for Lung Research (DZL), Biomedical Research in Endstage and Obstructive Lung Disease (BREATH) Research Network, Hannover, Germany; Institute of Immunology, Hannover Medical School, Hannover, Germany
Schaudien, Dirk (författare)
Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM), Hannover, Germany; Fraunhofer International Consortium for Anti-Infective Research (iCAIR), Hannover, Germany; Fraunhofer Cluster of Excellence Immune-Mediated Diseases, (CIMD), Hannover, Germany; Member of the German Center for Lung Research (DZL), Biomedical Research in Endstage and Obstructive Lung Disease (BREATH) Research Network, Hannover, Germany; Institute of Immunology, Hannover Medical School, Hannover, Germany
Oestereich, Lisa (författare)
Department of Virology, Bernhard-Nocht Institute for Tropical Medicine, Hamburg, Germany; German Center for Infectious Research (DZIF), Partner Site Hamburg-Lübeck-Borstel-Riems, Hamburg, Germany
Braun, Armin (författare)
Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM), Hannover, Germany; Fraunhofer International Consortium for Anti-Infective Research (iCAIR), Hannover, Germany; Fraunhofer Cluster of Excellence Immune-Mediated Diseases, (CIMD), Hannover, Germany; Member of the German Center for Lung Research (DZL), Biomedical Research in Endstage and Obstructive Lung Disease (BREATH) Research Network, Hannover, Germany; Institute of Immunology, Hannover Medical School, Hannover, Germany
Kunz, Stefan (författare)
Institute of Microbiology, University Hospital Center and University of Lausanne, Lausanne, Switzerland
Gerold, Gisa, 1979- (författare)
Umeå universitet,Institutionen för klinisk mikrobiologi,Wallenberg centrum för molekylär medicin vid Umeå universitet (WCMM),Department of Biochemistry & Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine Hannover, Hannover, Germany
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 (creator_code:org_t)
John Wiley & Sons, 2023
2023
Engelska.
Ingår i: Journal of Medical Virology. - : John Wiley & Sons. - 0146-6615 .- 1096-9071. ; 95:11
Relaterad länk:
https://doi.org/10.1...
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https://umu.diva-por... (primary) (Raw object)
https://urn.kb.se/re...
https://doi.org/10.1...
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  • Tidskriftsartikel (refereegranskat)
Abstract Ämnesord
Stäng  
  • The emerging viruses SARS-CoV-2 and arenaviruses cause severe respiratory and hemorrhagic diseases, respectively. The production of infectious particles of both viruses and virus spread in tissues requires cleavage of surface glycoproteins (GPs) by host proprotein convertases (PCs). SARS-CoV-2 and arenaviruses rely on GP cleavage by PCs furin and subtilisin kexin isozyme-1/site-1 protease (SKI-1/S1P), respectively. We report improved luciferase-based reporter cell lines, named luminescent inducible proprotein convertase reporter cells that we employ to monitor PC activity in its authentic subcellular compartment. Using these sensor lines we screened a small compound library in high-throughput manner. We identified 23 FDA-approved small molecules, among them monensin which displayed broad activity against furin and SKI-1/S1P. Monensin inhibited arenaviruses and SARS-CoV-2 in a dose-dependent manner. We observed a strong reduction in infectious particle release upon monensin treatment with little effect on released genome copies. This was reflected by inhibition of SARS-CoV-2 spike processing suggesting the release of immature particles. In a proof of concept experiment using human precision cut lung slices, monensin potently inhibited SARS-CoV-2 infection, evidenced by reduced infectious particle release. We propose that our PC sensor pipeline is a suitable tool to identify broad-spectrum antivirals with therapeutic potential to combat current and future emerging viruses.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Infektionsmedicin (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Infectious Medicine (hsv//eng)

Nyckelord

antiviral
arenavirus
broad-spectrum
emerging virus
furin
high-throughput screening
inducible sensor cell lines
inhibition
pandemic preparedness
proprotein convertase
SARS-CoV-2
SKI-1/S1P
viral GP cleavage

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