TY - JOUR

T1 - Labyrinthopeptins Exert Broad-Spectrum Antiviral Activity through Lipid-Binding-Mediated Virolysis

AU - Prochnow, Hans

AU - Rox, Katharina

AU - Suryanarayana Birudukota, N. V.

AU - Weichert, Loreen

AU - Hotop, Sven Kevin

AU - Klahn, Philipp

AU - Mohr, Kathrin

AU - Franz, Sergej

AU - Banda, Dominic H.

AU - Blockus, Sebastian

AU - Schreiber, Janine

AU - Haid, Sibylle

AU - Oeyen, Merel

AU - Martinez, Javier P.

AU - Süssmuth, Roderich D.

AU - Wink, Joachim

AU - Meyerhans, Andreas

AU - Goffinet, Christine

AU - Messerle, Martin

AU - Schulz, Thomas F.

AU - Kröger, Andrea

AU - Schols, Dominique

AU - Pietschmann, Thomas

AU - Brönstrup, Mark

N1 - Funding Information: Thomas Pietschmann was supported by funds from the Helmholtz Alberta initiative of infectious disease research (HAI-IDR). 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/MINEICO/FEDER, UE). Mark Brönstrup, Andreas Meyerhans, and Javier P. Martinez 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 Brön-strup 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 from the Helmholtz Center for Infection Research (HZI) and the Berlin Institute of Health (BIH). Sergej Franz was supported by the Infection Biology international Ph.D. program of Hannover Biomedical Research School.

PY - 2020/1/6

Y1 - 2020/1/6

N2 - 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. 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.

AB - 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. 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.

KW - Antivirals

KW - Dengue virus

KW - DENV

KW - Drug discovery

KW - Drug synergism

KW - Lanthipeptides

KW - Lipids

KW - Mechanism of action

KW - Phosphatidylethanolamine

KW - Zika virus

KW - ZIKV

UR - http://www.scopus.com/inward/record.url?scp=85077669810&partnerID=8YFLogxK

U2 - 10.1128/JVI.01471-19

DO - 10.1128/JVI.01471-19

M3 - Article

C2 - 31666384

AN - SCOPUS:85077669810

VL - 94

JO - Journal of virology

JF - Journal of virology

SN - 0022-538X

IS - 2

M1 - e01471-19

ER -