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

authored by

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

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 [t_1/2] 10.0 h), which designates them promising antiviral compounds acting by an unusual viral lipid targeting mechanism. I M P O R T A N C E 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.

Organisation(s)

Section Chemical Biology

External Organisation(s)

Helmholtz Centre for Infection Research (HZI)
TWINCORE Zentrum für Experimentelle und Klinische Infektionsforschung GmbH
Universität Pompeu Fabra (UPF)
Technische Universität Berlin
Catalan Institution for Research and Advanced Studies (ICREA)
Charité - Universitätsmedizin Berlin
Hannover Medical School (MHH)
Otto-von-Guericke University Magdeburg
German Center for Infection Research (DZIF)
KU Leuven

Type

Article

Journal

Journal of virology

Volume

94

ISSN

0022-538X

Publication date

06.01.2020

Publication status

Published

Peer reviewed

Yes

ASJC Scopus subject areas

Microbiology, Immunology, Insect Science, Virology

Sustainable Development Goals

SDG 3 - Good Health and Well-being

Electronic version(s)

https://doi.org/10.1128/JVI.01471-19 (Access: Closed)