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Peptides in oral diseases: state of the art

Alberta Lucchese1*
  • 1 Second University of Naples, Multidisciplinary Department of Medical-Surgical and Odontostomatological Specialties, Italy

Peptides are short aminoacid (aa) sequences that play crucial roles in fundamental cellular processes and alterations of which can induce/favorinfections, neuropsychiatric disorders, cardiovascular diseases, and cancer. Anti Microbial Peptides (AMPs), also called Host Defense Peptides (HDPs), have immunomodulatory properties and are produced by virtually all organisms (de la Fuente-Nunez et al., 2017). AMPs display different secondary structures, i.e., alpha-helixes, beta-sheets, coils, but nonetheless but share physico-chemical commonalities such as i) an overall positive charge due to their many Arg and Lys residues, and ii) a high percentage (~50%) of hydrophobic aa that facilitate their interaction with membranes and, then, their translocation into cells (Wang, 2014;de la Fuente-Nunez et al., 2017). Some AMPs are present in the oral cavity: β-Defensins, detected in the suprabasal layers of stratified epithelium; LL-37, present in neutrophils, gingival sulcus and saliva; Histatin and Lactoferrin detected in the saliva (Dale and Fredericks, 2005). As regard AMPs, the following points are worth of note: • β-defensin expression is regulated at the transcriptional level by interaction with pathogens (Diamond and Ryan, 2011). • Cathelicidins are found in the granules of neutrophils. The only human cathelicidin is hCAP-18 that is synthesized as a prepropeptide. Cleavage of hCAP-18 by proteinase 3 generates exocytosed leucine-leucine-37 (LL-37; so named for the first two amino acids and a total of 37 amino acids), which is released into the extracellular space (Sorensen et al., 2001). • Histatins are a family of histidine-rich low molecular weight proteins that are present in the saliva. Histatin-1 and histatin-3 are full-length products encoded by the genes HIS1 and HIS2, respectively, while the smaller members, histatin-2, -4, -5, -6, -7, -8, -9, -10, -11, -12, result from proteolytic cleavage of histatin-1 and -3 (Melino et al., 2014). • Lactoferrin (LF) consists of a polypeptide chain folded into 2 symmetrical lobes (N and C lobes) that are connected by a hinge region containing part of an α-helix. LF is a potent iron chelator and can sequester free iron from fluids and inflammed tissues. LF peptides are protein fragments released via proteolysis by the action of various proteolytic enzymes (Velliyagounder et al., 2018). Moreover, AMPs display anti-microbial, anti-fungal, anti-viral, wound healing, and immunomodulatory properties. ANTI-MICROBIAL PROPERTIES The anti-microbial properties are explained by the Shai-Matsuzaki-Huang model according to the following mechanistic steps: 1. AMPs interact with the bacterial membrane surface and cover it in a carpet-like manner by electrostatic attraction. Then, AMPs incorporate into the membrane by a permeation process that occurs only if there is a high local concentration of membrane-bound peptides. 2. Consequently, the membrane structure is then altered, with the formation of an opening within the bilayer. 3. AMPs and lipids migrate into the inner leaflet of the membrane through the pores. 4. The bacterial membrane collapses into fragments and lyses (Shai, 1999;Shental-Bechor et al., 2007). ANTI-FUNGAL PROPERTIES Anti-fungal AMPs may target either the main component of fungi cell wall (chitin) or intracellular components. The potent activity of HDPs appears to be due to their amphiphilic structure and to the ability to disrupt selectively microbial membranes by channel formation. New modes of action have been proposed for several of the HDPs. For example, the salivary anti-candida peptide histatin-5 might impair mitochondrial membrane polarity in yeast, in this way producing reactive oxygen species (ROS) that lead to cell death (Wang, 2014;Lakshmaiah Narayana and Chen, 2015;Menzel et al., 2017). ANTI-VIRAL PROPERTIES The diversity of viral species reflects a multitude of antiviral mechanisms exerted by AMPs. AMPs neutralize viruses by integrating themselves into the viral envelope or host cell membrane. I.e., LF inhibits HSV-1 binding to the host cell surface by competitive binding to viral glycosaminoglycans and inhibits viral post-attachment replication and cell-to-cell spreading. AMPs inhibit many steps in viral entry, but also post-entry effects have been described (Wilson et al., 2013). WOUND HEALING AMPs also promote wound healing. I.e., Histatin-1 can stimulate keratinocytes and endothelial cell migration mediated by the activation of the ERK1/2 signal transduction pathway (Torres et al., 2018). IMMUNOMODULATORY AMPs can contribute to host defence and innate immunity by exerting a chemotactic activity for T-cells, dendritic cells, neutrophils, and mast cells. In addition, AMPs also contribute to enhance the adaptive immune response since binding of AMPs to antigens may facilitate the delivery of bound antigen to antigen-presenting cells, in some cases via specific receptors. These interactions enhance the immunogenicity of the bound antigen in an adjuvant-like fashion (Diamond and Ryan, 2011). AMPs and CANCER AMPs can have antineoplastic and/or pro-neoplastic functions. Nishimura et al. found that the pro- or anti-tumour activity of defensins is concentration-dependent. I.e., HD-1 at low concentration (∼8 μg/ml) promoted proliferation of oral cancer cells, whereas at high concentration (50μg/ml) HD-1 induced cell death, thus suggesting a non-specific response of cancer cells to the peptide (Nishimura et al., 2004). Human cathelicidins show antineoplastic activities against oral cancer cells. The active domain of LL-37 causes mitochondrial depolarization, leading to apoptosis in a caspase-independent fashion in human OSCC cells. Interestingly, LL-37 is unable to induce cell death of normal human gingival fibroblasts, suggesting that hCAP-18 may be a useful anti-tumour therapeutic agent for treatment of OSCC (Jin and Weinberg, 2018). AMPs are also potential biomarkers for oral cancer. hBD-3 is overexpressed in early stages of OSCC, while hBD-2 expression is low. This suggests that the expression profile of hBDs may associate with early events in OSCC. Moreover, hBD-3 overexpression in OSCC tissues has been shown to associate with lymph node metastasis (Jin and Weinberg, 2018). PEPTIDE AS MODULATORS OF PROTEIN-PROTEIN INTERACTION. Another field of interest in examining peptide utilization to target oral diseases is represented by peptides able to regulate biological interactions: peptide modulators of protein-protein interaction (PPi). Examples of this kind of peptides are: - Survivin derived peptide. Survivin is highly expressed in cancer cells. It works as an inhibitor of apoptosis protein (IAP) protein, and it is important during cell division. T-cells from patients with cancer specifically recognize survivin–derived peptide epitopes that derive from the degradation of intracellular survivin protein and bind to HLAclass I molecules. Hence, as T cells in patients with cancer specifically recognize survivin, immunomediated tumour destruction is emerging as an interesting modality to treat cancer. A peptide derived from survivin-2B80-88 (AYACNTSTL) is recognized by CD8+ CTL in the context of HLA-A24 molecules. The CTL specific for this peptide are induced from PBMC in patients with oral cancers (Kobayashi et al., 2009;Miyazaki et al., 2011). - Desmoglein 3 derived peptide. Using computer-assisted analyses and an epitope mapping approach, it could be possible to identify a Dsg3 peptide sequence that represents an epitope in Pemphigus vulgaris autoimmunity (Lucchese et al., 2004;Lucchese and Sinha, 2016). At a functional level, synthesize and administer this peptide sequence could play a therapeutic role in the modulation of autoimmunity: the synthetic peptide that binds to the MHC molecules has to mimic the natural self peptide sequence, and it has to lack the inflammatory response elicited by the native peptide. Moreover, although the primary structure of the artificial peptide must structurally resemble that of the self peptide that drives and/or sustains the autoimmune response, the conformational change of the artificial peptide-that is not identical three-dimensionally-makes the ligand/receptor binding that would lead to activation of APC or T cells either unproductive or partly ineffective. As a consequence, the artificial peptide will inhibit autoimmune cell activation (Schall et al., 2012). CONCLUSIONS The oral cavity is a target for a large number of infections and pathological conditions. Peptides are immunotherapeutic tools recognized for being highly selective and efficacious and, at the same time, relatively safe and well tolerated. Clinical applications of peptide-based approaches might contribute to more favorable outcomes in recalcitrant oral infections and oral squamous cell carcinoma. Regarding autoimmunity, successful data have been reported in numerous mouse models of autoimmune inflammation, yet relatively few clinical trials based on synthetic peptides are currently underway. Future scientific research and clinical trials will advance the current knowledge about the conceptual framework of peptide interaction with oral diseases and pathogens (Schall et al., 2012;Melino et al., 2014;Fosgerau and Hoffmann, 2015).

References

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Keywords: Peptides, Defensins, LL37, Histatins, Lactoferrin, Oral diseases

Conference: 5th National and 1st International Symposium of Italian Society of Oral Pathology and Medicine., Ancona, Italy, 19 Oct - 20 Oct, 2018.

Presentation Type: oral presentation

Topic: Oral Diseases

Citation: Lucchese A (2019). Peptides in oral diseases: state of the art. Front. Physiol. Conference Abstract: 5th National and 1st International Symposium of Italian Society of Oral Pathology and Medicine.. doi: 10.3389/conf.fphys.2019.27.00090

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Received: 27 Nov 2018; Published Online: 09 Dec 2019.

* Correspondence: Prof. Alberta Lucchese, Second University of Naples, Multidisciplinary Department of Medical-Surgical and Odontostomatological Specialties, Naples, Campania, 80138, Italy, marcomascitti86@hotmail.it