Activity of Potent and Selective Host Defense Peptide Mimetics in Mouse Models of Oral Candidiasis

Ryan, Lisa K.; Freeman, Katie B.; Masso-Silva, Jorge A; Falkovsky, Klaudia; Aloyouny, Ashwag; Markowitz, Kenneth; Hise, Amy G.; Fatahzadeh, Mahnaz; Scott, Richard W.; Diamond, Gill

doi:10.1128/aac.02649-13

Cited by 28 publications

(40 citation statements)

References 45 publications

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“…While LL-37 exerts its antiviral activity via a direct effect on the virion in the case of this paper and others, cathelicidins in general (He et al, 2018) and LL-37 specifically (Barlow et al, 2014a) have also been shown to enhance other methods of innate antiviral immunity, namely interferon expression. Current work in endogenous antimicrobial peptide expression (Dhawan et al, 2015; Klein-Patel et al, 2006; Rivas-Santiago et al, 2005; Ryan et al, 2011; Ryan and Diamond, 2017) and small molecule mimetics of antimicrobial peptides (Beckloff et al, 2007; Menzel et al, 2017; Ryan et al, 2014) would potentially serve as methods to prevent not only KSHV infection, but also other viral infections of the oral cavity.…”

Section: Discussionmentioning

confidence: 99%

LL-37 disrupts the Kaposi's sarcoma-associated herpesvirus envelope and inhibits infection in oral epithelial cells

2018

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Oral epithelial cells (OECs) represent the first line of defense against viruses that are spread via saliva, including Kaposi's sarcoma-associated herpesvirus (KSHV). Infection of humans by KSHV and viral pathogenesis begins by infecting OECs. One method OECs use to limit viral infections in the oral cavity is the production of antimicrobial peptides (AMPs), or host defense peptides (HDPs). However, no studies have investigated the antiviral activities of any HDP against KSHV. The goal of this study was to determine the antiviral activity of one HDP, LL-37, against KSHV in the context of infecting OECs. Our results show that LL-37 significantly decreased KSHV's ability to infect OECs in both a structure- and dose-dependent manner. However, this activity does not stem from affecting OECs, but instead the virions themselves. We found that LL-37 exerts its antiviral activity against KSHV by disrupting the viral envelope, which can inhibit viral entry into OECs. Our data suggest that LL-37 exhibits a marked antiviral activity against KSHV during infection of oral epithelial cells, which can play an important role in host defense against oral KSHV infection. Thus, we propose that inducing LL-37 expression endogenously in oral epithelial cells, or potentially introducing as a therapy, may help restrict oral KSHV infection and ultimately KSHV-associated diseases.

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Section: Discussionmentioning

confidence: 99%

LL-37 disrupts the Kaposi's sarcoma-associated herpesvirus envelope and inhibits infection in oral epithelial cells

2018

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“…The recently reported library of small synthetic peptide mimics by Diamond and co‐workers was also shown to contain selected promising compounds active against oral Candida strains and superior to nystatin in a mouse model. The best effect for those compounds was seen in a non‐immunosuppressed steroid‐free oral C. albicans candidiasis mouse model …”

Section: Introductionmentioning

confidence: 99%

“…The best effect for those compounds was seen in a non-immunosuppressed steroid-free oral C. albicans candidiasis mouse model. 30 We recently reported on the antifungal activity of small synthetic AMPs with a design based on the pharmacophore reported for cationic synthetic lactoferricin mimetics. 32 The bioactivity for these short peptides relies on a balance between hydrophobic bulk and cationic charge.…”

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confidence: 99%

Development and evaluation of cationic amphiphilic antimicrobial 2,5‐diketopiperazines

Labriere

Kondori

Caous

et al. 2018

Journal of Peptide Science

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Both pathogenic bacteria and fungi are developing resistance to common antimicrobial treatment at an alarming rate. To counteract this development, it is of essence to develop new classes of antimicrobial agents. One such class is antimicrobial peptides, most of which are derived from the innate immune system. In this study, a series of novel 2,5‐diketopiperazines were designed, synthesized, and evaluated for their antimicrobial abilities. The compounds were designed to probe the pharmacophore dictated for short linear mimics of antimicrobial cationic peptides, and as such, the compounds contain a range of cationic and hydrophobic functionalities. Several of the prepared compounds displayed high antimicrobial activities toward bacteria and also against human pathogenic fungi. Of particular interest was the high activity toward fungal strains with an inherent increased resistance toward conventional antifungal agents. The most effective compounds displayed inhibition of Candida glabrata and Candida krusei growth at concentrations between 4 and 8 μg/mL, which is comparable to commercial antifungal agents in use. Structure activity relationship studies revealed a similar dependence on cationic charge and the volume of the hydrophobic bulk as for linear cationic antimicrobial peptides. Finally, the hemolytic activity of selected compounds was evaluated, which revealed a potential to produce active compounds with attenuation of unwanted hemolysis. The findings highlight the potential of cyclic cationic amphiphilic peptidomimetics as a class of promising compounds for the treatment of infections caused by microorganisms with an increased resistance to conventional antimicrobial agents.

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“…It was recently discovered that recombinant mBD1 has direct fungicidal activity via inhibition of growth and germ tube generation (5). In another study, treatment of Candida infected mice with a non-peptide mimetic of mBD1 was shown to substantially reduce fungal burdens in the oral cavity, though the impact on innate immune activation was not studied (18). Other murine defensins have also been shown to have antifungal properties including mBD3 which induces perforation of the microbial cell wall, resulting in cell lysis and can amplify the antifungal properties of amphotericin (19).…”

Section: Introductionmentioning

confidence: 99%

β-Defensin 1 Plays a Role in Acute Mucosal Defense against Candida albicans

Tomalka

Azodi

Narra

et al. 2015

The Journal of Immunology

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Candida is an opportunistic fungal pathogen that colonizes the mucosal tract of humans. Pathogenic infection occurs in the presence of conditions causing perturbations to the commensal microbiota or host immunity. Early innate immune responses by the epithelium, including antimicrobial peptides (AMPs) and cytokines, are critical for protection against overgrowth. Reduced salivary AMP levels are associated with oral Candida infection and certain AMPs, including human beta-defensins 1 - 3, have direct fungicidal activity. Here we demonstrate that murine β-Defensin 1 (mBD1) is important for control of early mucosal Candida infection and plays a critical role in the induction of innate inflammatory mediators. Mice deficient in mBD1 exhibit elevated oral and systemic fungal burdens as compared to wild-type mice. Neutrophil infiltration to the sites of mucosal Candida invasion, an important step in limiting fungal infection, is significantly reduced in mBD1 deficient mice. These mice also exhibit defects in the expression of other antimicrobial peptides, including mBD2 and mBD4, which may have direct anti-Candida activity. We also show that mBD1 deficiency impacts the production of important anti-fungal inflammatory mediators including IL-1β, IL-6, KC, and IL-17. Collectively, these studies demonstrate a role for the mBD1 peptide in early control of Candida infection in a murine model of mucosal candidiasis, as well as on the modulation of host immunity through augmentation of leukocyte infiltration and inflammatory gene induction.

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Activity of Potent and Selective Host Defense Peptide Mimetics in Mouse Models of Oral Candidiasis

Cited by 28 publications

References 45 publications

LL-37 disrupts the Kaposi's sarcoma-associated herpesvirus envelope and inhibits infection in oral epithelial cells

LL-37 disrupts the Kaposi's sarcoma-associated herpesvirus envelope and inhibits infection in oral epithelial cells

Development and evaluation of cationic amphiphilic antimicrobial 2,5‐diketopiperazines

β-Defensin 1 Plays a Role in Acute Mucosal Defense against Candida albicans

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