PMID- 37975336 OWN - NLM STAT- MEDLINE DCOM- 20231127 LR - 20231208 IS - 1096-9071 (Electronic) IS - 0146-6615 (Linking) VI - 95 IP - 11 DP - 2023 Nov TI - Luminescent reporter cells enable the identification of broad-spectrum antivirals against emerging viruses. PG - e29211 LID - 10.1002/jmv.29211 [doi] AB - 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. CI - (c) 2023 The Authors. Journal of Medical Virology published by Wiley Periodicals LLC. FAU - Low, Karin AU - Low K AUID- ORCID: 0000-0002-5052-3892 AD - Department of Biochemistry & Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine Hannover, Hannover, Germany. AD - Institute of Microbiology, University Hospital Center and University of Lausanne, Lausanne, Switzerland. FAU - Moller, Rebecca AU - Moller R AUID- ORCID: 0000-0001-7872-6192 AD - Department of Biochemistry & Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine Hannover, Hannover, Germany. FAU - Stegmann, Cora AU - Stegmann C AUID- ORCID: 0000-0003-4408-4026 AD - Department of Biochemistry & Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine Hannover, Hannover, Germany. FAU - Becker, Miriam AU - Becker M AUID- ORCID: 0000-0002-3634-066X AD - Department of Biochemistry & Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine Hannover, Hannover, Germany. FAU - Rehburg, Laura AU - Rehburg L AD - Department of Biochemistry & Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine Hannover, Hannover, Germany. FAU - Obernolte, Helena AU - Obernolte H AD - Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM), Hannover, Germany. AD - Fraunhofer International Consortium for Anti-Infective Research (iCAIR), Hannover, Germany. AD - Fraunhofer Cluster of Excellence Immune-Mediated Diseases, (CIMD), Hannover, Germany. AD - Member of the German Center for Lung Research (DZL), Biomedical Research in Endstage and Obstructive Lung Disease (BREATH) Research Network, Hannover, Germany. AD - Institute of Immunology, Hannover Medical School, Hannover, Germany. FAU - Schaudien, Dirk AU - Schaudien D AUID- ORCID: 0000-0001-7398-7262 AD - Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM), Hannover, Germany. AD - Fraunhofer International Consortium for Anti-Infective Research (iCAIR), Hannover, Germany. AD - Fraunhofer Cluster of Excellence Immune-Mediated Diseases, (CIMD), Hannover, Germany. AD - Member of the German Center for Lung Research (DZL), Biomedical Research in Endstage and Obstructive Lung Disease (BREATH) Research Network, Hannover, Germany. AD - Institute of Immunology, Hannover Medical School, Hannover, Germany. FAU - Oestereich, Lisa AU - Oestereich L AUID- ORCID: 0000-0003-0098-7485 AD - Department of Virology, Bernhard-Nocht Institute for Tropical Medicine, Hamburg, Germany. AD - German Center for Infectious Research (DZIF), Partner Site Hamburg-Lubeck-Borstel-Riems, Hamburg. FAU - Braun, Armin AU - Braun A AUID- ORCID: 0000-0002-1142-1463 AD - Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM), Hannover, Germany. AD - Fraunhofer International Consortium for Anti-Infective Research (iCAIR), Hannover, Germany. AD - Fraunhofer Cluster of Excellence Immune-Mediated Diseases, (CIMD), Hannover, Germany. AD - Member of the German Center for Lung Research (DZL), Biomedical Research in Endstage and Obstructive Lung Disease (BREATH) Research Network, Hannover, Germany. AD - Institute of Immunology, Hannover Medical School, Hannover, Germany. FAU - Kunz, Stefan AU - Kunz S AD - Institute of Microbiology, University Hospital Center and University of Lausanne, Lausanne, Switzerland. FAU - Gerold, Gisa AU - Gerold G AUID- ORCID: 0000-0002-1326-5038 AD - Department of Biochemistry & Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine Hannover, Hannover, Germany. AD - Department of Clinical Microbiology, Umea University, Sweden. AD - Wallenberg Centre for Molecular Medicine (WCMM), Umea University, Sweden. LA - eng GR - German Federal Ministry for Education and Research/ GR - Niedersachsisches Ministerium fur Wissenschaft und Kultur/ GR - Knut and Allice Wallenberg foundation/ GR - Schweizerischer Nationalfonds zur Forderung der Wissenschaftlichen Forschung/ PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - United States TA - J Med Virol JT - Journal of medical virology JID - 7705876 RN - EC 3.4.21.75 (Furin) RN - 0 (Viral Envelope Proteins) RN - 906O0YJ6ZP (Monensin) RN - 0 (Antiviral Agents) SB - IM MH - Humans MH - *Furin/metabolism MH - Viral Envelope Proteins/genetics MH - Monensin/metabolism/pharmacology MH - *Arenavirus/genetics/metabolism MH - Antiviral Agents/therapeutic use OTO - NOTNLM OT - SARS-CoV-2 OT - SKI-1/S1P OT - antiviral OT - arenavirus OT - broad-spectrum OT - emerging virus OT - furin OT - high-throughput screening OT - inducible sensor cell lines OT - inhibition OT - pandemic preparedness OT - proprotein convertase OT - viral GP cleavage EDAT- 2023/11/17 15:31 MHDA- 2023/11/27 12:44 CRDT- 2023/11/17 06:32 PHST- 2023/09/29 00:00 [revised] PHST- 2023/02/28 00:00 [received] PHST- 2023/10/21 00:00 [accepted] PHST- 2023/11/27 12:44 [medline] PHST- 2023/11/17 15:31 [pubmed] PHST- 2023/11/17 06:32 [entrez] AID - 10.1002/jmv.29211 [doi] PST - ppublish SO - J Med Virol. 2023 Nov;95(11):e29211. doi: 10.1002/jmv.29211.