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

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 [t1/2] = 10.0 h), which designates them 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 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.

Chikungunya and Zika Viruses: Co-Circulation and the Interplay between Viral Proteins and Host Factors

“…Cell lines pretreated with different concentrations of the compounds before infection by CHIKV and ZIKV inhibit virus infection in the low micromolar-to-nanomolar range. A study of the peptide’s mechanism using 11 species of adsorbed lipids demonstrated that the virolysis effect occurred through the binding of labyrinthopeptins and lipid phosphatidylethanolamine to the viral membrane [ 254 ]. However, in vivo experiments of labyrinthopeptins are still needed.…”

Drug Development for the Management of Corona Viruses: Insights from Natural Antiviral Agents

“…209 Labyrinthopeptins A1 and A2, were found to inhibit the proliferation of many enveloped viruses including dengue virus, Zika virus, West Nile virus, hepatitis C virus, chikungunya virus, Kaposi's sarcoma-associated herpes virus, cytomegalovirus, and herpes simplex virus with mechanism of action showing that it induced virolytic effect through binding to the viral membrane lipid phosphatidylethanolamine (PE). 210 Several derivatives are currently available for treating different viral infections, 211 which makes it a promising compound for assessment against coronavirus and/or SARS-CoV-2 infection.…”

Antiviral activities and applications of ribosomally synthesized and post-translationally modified peptides (RiPPs)

“…LabyA2 also showed antiviral activity against HSV, but was at least tenfold less potent than Laby A1 [ 43 ]. Recently, a study reported that Laby A1/A2 can inhibit the infection of cells by a series of enveloped viruses, including Dengue, Zika, West Nile, Hepatitis C, Chikungunya and Karposi’s Sarcoma-associated Herpes virus, with 50% inhibitory concentration (IC 50 ) in the low micromolar to nanomolar range, and it was clarified that Laby A1/A2 specifically interact with the envelope lipid PE (rather than sphingomyelin with an ethanolamine head group, phosphatidylcholine, or other eight lipid species tested), thereby disrupting the membrane to exert their antiviral effect [ 37 ]. Subsequently, the result of another mechanistic study supported the notion that an interaction between Laby A1/A2 and PE is critical for their antiviral activity, and verified that labyrinthopeptins exert virolytic effect on Respiratory syncytial virus (RSV) by disrupting virus particle membrane integrity [ 44 ].…”

“…It is worth noting that Laby A1/A2 have advantages over duramycin and cinnamycin in low cytotoxicity and lack of adverse drug effects. Thus, labyrinthopeptins are promising antivirals to be developed with efficacy against a broad range of viruses, and with favorable therapeutic index [ 37 , 44 ].…”