title: The lantibiotic peptide labyrinthopeptin A1 demonstrates broad anti-HIV and anti-HSV activity with potential for microbicidal applications.
abstract: Lantibiotics are peptides, produced by bacteria, that contain the noncanonical amino acid lanthionine and many of them exhibit antibacterial activities. The labyrinthopeptin A1 (LabyA1) is a prototype peptide of a novel class of carbacyclic lantibiotics. Here, we extensively evaluated its broad-spectrum activity against HIV and HSV in vitro, studied its mechanism of action and evaluated potential microbicidal applications. LabyA1 exhibited a consistent and broad anti-HIV activity (EC50s: 0.70-3.3 µM) and anti-HSV activity (EC50s: 0.29-2.8 µM) in cell cultures. LabyA1 also inhibited viral cell-cell transmission between persistently HIV-infected T cells and uninfected CD4(+) T cells (EC50∶2.5 µM) and inhibited the transmission of HIV captured by DC-SIGN(+)-cells to uninfected CD4(+) T cells (EC50∶4.1 µM). Time-of-drug addition studies revealed that LabyA1 acts as an entry inhibitor against HIV and HSV. Cellular and virus binding studies combined with SPR/FLIPR technology showed that LabyA1 interacted with the HIV envelope protein gp120, but not with the HIV cellular receptors. LabyA1 also demonstrated additive to synergistic effects in its anti-HIV-1 and anti-HSV-2 activity with anti(retro)viral drugs in dual combinations such as tenofovir, acyclovir, saquinavir, raltegravir and enfuvirtide. LabyA1 can be considered as a novel lead peptide as it had profound antiviral activity against HIV and HSV. Pre-treatment of PBMCs with LabyA1 neither increased the expression of the activation markers CD69 and CD25, nor enhanced HIV replication, nor significantly induced various inflammatory cytokines/chemokines. LabyA1 also did not affect the growth of vaginal Lactobacilli populations. Based on the lack of toxicity on the vaginal Lactobacillus strains and its synergistic/additive profile in combination with clinically approved anti(retro)virals, it deserves further attention as a potential microbicide candidate in the prevention of sexual transmitted diseases.
authors.affiliation: Rega Institute for Medical Research, University of Leuven, Leuven, Belgium.
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Férir
authors.forename: Mariya I
authors.initials: MI
authors.lastname: Petrova
authors.forename: Graciela
authors.initials: G
authors.lastname: Andrei
authors.forename: Dana
authors.initials: D
authors.lastname: Huskens
authors.forename: Bart
authors.initials: B
authors.lastname: Hoorelbeke
authors.forename: Robert
authors.initials: R
authors.lastname: Snoeck
authors.forename: Jos
authors.initials: J
authors.lastname: Vanderleyden
authors.forename: Jan
authors.initials: J
authors.lastname: Balzarini
authors.forename: Stefan
authors.initials: S
authors.lastname: Bartoschek
authors.forename: Mark
authors.initials: M
authors.lastname: Brönstrup
authors.forename: Roderich D
authors.initials: RD
authors.lastname: Süssmuth
authors.forename: Dominique
authors.initials: D
authors.lastname: Schols
mesh_terms: D019380:Anti-HIV Agents / Q000494:pharmacology*; D001430:Bacteriocins / Q000737:chemistry / Q000494:pharmacology*; D015704:CD4 Antigens / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000378:metabolism; D024882:Drug Resistance, Viral / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects / Q000382:microbiology / Q000473:pathology; D005260:Female; D015726:Giant Cells / Q000187:drug effects; D015699:HIV Envelope Protein gp120 / Q000378:metabolism; D015658:HIV Infections / Q000473:pathology / Q000821:virology; D015497:HIV-1 / Q000187:drug effects* / Q000302:isolation & purification / Q000502:physiology; D006801:Humans; D007700:Kinetics; D007778:Lactobacillus / Q000187:drug effects* / Q000254:growth & development; D037181:Lectins, C-Type / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000821:virology; D009561:Nisin / Q000378:metabolism / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D019718:Receptors, CXCR4 / Q000378:metabolism; D054380:Receptors, CXCR5 / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D018139:Simplexvirus / Q000187:drug effects* / Q000502:physiology; D014621:Vagina / Q000382:microbiology / Q000473:pathology; D053586:Virus Internalization / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
chemical_list: D019380:Anti-HIV Agents; D001430:Bacteriocins; D015704:CD4 Antigens; D015815:Cell Adhesion Molecules; D015699:HIV Envelope Protein gp120; D037181:Lectins, C-Type; D009561:Nisin; D019718:Receptors, CXCR4; D054380:Receptors, CXCR5; D011956:Receptors, Cell Surface; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin; C582102:labyrinthopeptin A1, Actinomadura namibiensis