Labyrinthopeptins exert broad-spectrum antiviral activity through lipid-binding-mediated virolysis

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• dc.contributor.author Prochnow, Hans
• dc.contributor.author Prado Martínez, Javier, 1987-
• dc.contributor.author Meyerhans, Andreas
• dc.contributor.author Brönstrup, Mark
• dc.date.accessioned 2019-12-05T10:47:36Z
• dc.date.issued 2020
• dc.description.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, Karposi's Sarcoma-associated Herpes virus, Cytomegalovirus, and Herpes Simplex virus, in the low μM to nM 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 IC10-IC90 values of the compounds. Time-resolved experiments with large unilamellar vesicles (LUVs) reveal that membrane lipid raft compositions (PC/PE/Chol/SM (17:10:33:40)) are particularly sensitive to labyrinthopeptins compared 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 (t1/2= 10.0 h), which designates them as 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 as well as (re-)emerging species - has gained attention, especially for the treatment of viral co-infections. 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, Karposi's Sarcoma-associated Herpes virus, or Cytomegalovirus. Labyrinthopeptins bind to viral phosphatidylethanolamine and induce virolysis without exerting cytotoxicity to host cells. This represents a novel and unusual mechanism to tackle medically relevant viral infections.
• dc.description.sponsorship Andreas Meyerhans and Javier P. Martinez were supported by a grant from the Spanish Ministry of Economy, Industry and Competitiveness and FEDER grant no. SAF2016-75505-R (AEI/MINEIC/FEDER, UE). Mark Brönstrup, Andreas Meyerhans and Javier P. Martinez would like to acknowledge a networking contribution from the COST Action CM1407 “Challenging organic syntheses inspired by nature – from natural products chemistry to drug discovery”. Martin Messerle and Thomas F. Schulz were supported by funding from DZIF (project 07.802 TTU IICH). Christine Goffinet, Thomas Pietschmann and Mark Brönstrup were supported by a grant provided by “Innovationsfonds der Helmholtz-Zentren”. Christine Goffinet was supported by a DFG grant within German African Cooperation Projects in Infectiology (GO2153/3-1) and by funding of the Helmholtz Center for Infection Research (HZI) and of Berlin Institute of Health (BIH). Sergej Franz was supported by the Infection Biology international PhD program of Hannover Biomedical Research School
• dc.format.mimetype application/pdf
• dc.identifier.citation Prochnow H, Rox K, Birudukota NVS, Weichert L, Hotop SK, Klahn P et al. Labyrinthopeptins exert broad-spectrum antiviral activity through lipid-binding-mediated virolysis. J Virol. 2020;94(2):e01471-19. DOI: 10.1128/JVI.01471-19
• dc.identifier.doi http://dx.doi.org/10.1128/JVI.01471-19
• dc.identifier.issn 0022-538X
• dc.identifier.uri http://hdl.handle.net/10230/43107
• dc.language.iso eng
• dc.publisher American Society for Microbiology
• dc.relation.ispartof Journal of Virology. 2020;94(2):e01471-19
• dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/SAF2016-75505-R
• dc.rights © American Society for Microbiology
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.subject.other Virosis
• dc.subject.other Medicaments
• dc.title Labyrinthopeptins exert broad-spectrum antiviral activity through lipid-binding-mediated virolysis
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/acceptedVersion