Peptides of the Constant Region of Antibodies Display Fungicidal Activity

Abstract

Synthetic peptides with sequences identical to fragments of the constant region of different classes (IgG, IgM, IgA) of antibodies (Fc-peptides) exerted a fungicidal activity in vitro against pathogenic yeasts, such as Candida albicans , Candida glabrata , Cryptococcus neoformans , and Malassezia furfur , including caspofungin and triazole resistant strains. Alanine-substituted derivatives of fungicidal Fc-peptides, tested to evaluate the critical role of each residue, displayed unaltered, increased or decreased candidacidal activity in vitro . An Fc-peptide, included in all human IgGs, displayed a therapeutic effect against experimental mucosal and systemic candidiasis in mouse models. It is intriguing to hypothesize that some Fc-peptides may influence the antifungal immune response and constitute the basis for devising new antifungal agents.

Dissecting the Structure-Function Relationship of a Fungicidal Peptide Derived from the Constant Region of Human Immunoglobulins

“…In particular, the IgG1-derived Fc N10K peptide (NQVS LTCLVK) turned out to be active in vitro at micromolar concentrations against several fungi, including multidrug-resistant strains, and protected mice against experimental systemic and mucosal candidiasis, being devoid of hemolytic, cytotoxic, and genotoxic effects. In addition, circular-dichroism (CD) studies proved that the N10K peptide self-aggregates, forming ␤-sheet structures in few hours after solution, and electron micrographs confirmed the presence of a network of fibril-like structures (9). These and previous studies pointed to a possible correlation between the self-aggregation property of bioactive peptides and in vivo therapeutic efficacy (11).…”

“…These and previous studies pointed to a possible correlation between the self-aggregation property of bioactive peptides and in vivo therapeutic efficacy (11). Alanine substitution derivatives (ASDs) of the N10K peptide, obtained by the replacement of each amino acid with alanine, revealed variable anti-Candida activities in vitro (9).…”

“…The in vitro activities of the N10K peptide and selected ASDs against C. albicans SC5314 were evaluated at different times (30, 60, 120, 240, and 360 min) by CFU assays as previously described (9). The selected peptides were used at their minimal fungicidal concentrations, previously assessed by CFU assays.…”

“…During elution, the optical absorbances at 495 and 215 nm were monitored in order to select peptidecontaining fractions and to calculate the peptide concentration. After lyophilization, the powders of each fraction were dissolved in dimethyl sulfoxide, then diluted in sterile water to a proper concentration, and assayed for candidacidal activity as previously described (9). Active fractions were stored at 4°C until use.…”

“…In previous studies, it was demonstrated that irrespective of the specificity of the native Ab for a given antigen, peptides related to Ab complementaritydetermining regions may exert differential in vitro, ex vivo, and in vivo antimicrobial, antiviral, antitumor, and immunomodulatory activities (4)(5)(6)(7)(8). Similarly, synthetic peptides representing fragments of the constant region of Abs (Fc peptides) were also reported to display fungicidal and/or immunomodulatory activities in vitro and/or in vivo, regardless of the isotype of the relevant Ab (9,10). In particular, the IgG1-derived Fc N10K peptide (NQVS LTCLVK) turned out to be active in vitro at micromolar concentrations against several fungi, including multidrug-resistant strains, and protected mice against experimental systemic and mucosal candidiasis, being devoid of hemolytic, cytotoxic, and genotoxic effects.…”