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.

Lantibiotics produced by Actinobacteria and their potential applications (a review)

“…Additive or synergistic effects were also demonstrated between LabA1 and antiviral drugs already used in the clinic (tenofovir, acyclovir, saquinavir, raltegravir and enfuvirtide). Therefore, LabA1 presents favourable properties that qualify its application in prevention and control of transmission of sexual diseases caused by HIV and HSV [16]. On the other hand, although LabA2 showed only a moderate anti-HSV activity and no anti-HIV activity [16,26], it presents a potent antipain activity [26], as also observed for NAI-112.…”

“…They are usually small peptides (<10 kDa) which are cationic and amphipathic [9][10][11][12]. Actinobacterial bacteriocins inhibit the growth of species related to the producer, such as michiganin A [13], although many of them possess a broad spectrum of inhibitory activity that includes non-related bacteria (microbisporicin), protozoans (thiostrepton), yeasts and fungi (cinnamycin) and viruses (labyrinthopeptin A1 and duramycin) [14][15][16][17][18]. In addition to antimicrobial activity, some actinobacterial bacteriocins and their semisynthetic derivatives also exhibit anti-inflammatory [19][20][21], anti-allergic [20], antitumour [22][23][24] and antinociceptive activities [25,26], and may also act in blood pressure regulation [19,27].…”

Antiviral drug discovery: broad-spectrum drugs from nature

“…Labyrinthopeptin A1 (LabyA1) (16) belongs to a novel class of carbacyclic lantibiotics 251 , 252 that was isolated from the actinomycete Actinomadura namibiensis. LabyA1 was recently shown to inhibit both HIV and HSV at sub-micromolar concentrations in vitro 234,235 . The compound is suggested to block viral entry by interacting with viral envelopes and to prevent cell-to-cell transmission.…”

Herpes simplex virus 2 infection: molecular association with HIV and novel microbicides to prevent disease

“…(Table 2). Labyrinthopeptin A1 is a carbacyclic lantibiotic with potent activity against HIV and HSV in vitro, capable of acting synergistically with acyclovir and tenofovir, within others [180]. PD 404,182, on the other hand, is capable of affecting the integrity of HIV and HSV through its interaction with viral protein components [181].…”