Remineralisation Potential of Self-assembling Peptide (P11-4) Compared to Other Remineralising Agents: A Narrative Review
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Dana Alsenan,
11564, Airport Road, Riyadh, Saudi Arabia.
E-mail: Aauh62963@gmail.com
Dental caries is a chronic infectious disease that affects the hard tissues of the teeth, primarily the enamel. Remineralisation involves depositing minerals back into demineralised enamel, repairing the damage, and preventing the formation of caries. Self-Assembling Peptide (SAP) P11-4 is a promising new remineralisation agent that mimics the natural process of remineralising dental enamel. It is a biomimetic peptide that binds to the surface of demineralised enamel, forming a three-dimensional network that supports mineral deposition and induces the production of reparative proteins. P11-4 is still in the early stages of development, but it has the potential to revolutionise the treatment of dental caries. SAP P11-4 has been shown to be safe and effective in remineralising early carious lesions. However, there is insufficient evidence to conclude that SAP P11-4 is more effective than other remineralising agents, such as fluoride, Casein Phosphopeptide-Amorphous Calcium Phosphate (CPP-ACP), and Silver Diamine Fluoride (SDF). The present review focuses on recent studies discussing the remineralisation potential of SAP P11-4 and compares it to other available remineralising agents. Overall, the review suggests that SAP P11-4 is a promising new remineralisation agent that is effective in treating early carious lesions. However, further research is needed to compare its effectiveness to other remineralisation agents and assess its long-term efficacy.
Dental caries, Fluorides, Peptides, Tooth remineralisation
Dental caries is a chronic infectious disease that affects the hard tissues of the teeth, primarily the enamel (1). It is caused by the action of acids produced by bacteria that reside in the mouth. These acids demineralise the enamel, leading to the formation of caries (1). In recent decades, the dental profession has shown interest in remineralisation. The term “remineralisation” refers to the process by which minerals are redeposited into the demineralised enamel, repairing the damage and preventing caries formation (1). The management of caries is shifting towards a minimally invasive approach, which emphasises prevention, reduction, and reversal of incipient caries lesions. Fluoride can interact with saliva at the surface and subsurface of the enamel to promote remineralisation through the formation of fluorhydroxyapatite (2). However, current fluoride therapies have demonstrated limitations, particularly in the treatment of caries that have already manifested as white spots (2).
White Spot Lesions (WSLs) are the earliest clinical manifestations of enamel demineralisation (3). Remineralisation therapy, which aims to restore lost minerals to the tooth enamel, is a growing trend in treating WSLs (3). Several remineralising agents are available, including fluoride, calcium phosphate, Casein Phosphopeptide-Amorphous Calcium Phosphate with Fluoride (CPP-ACPF), and SDF (2). Although all these mentioned materials are referred to as remineralising agents, the mechanism of action for each is different. Fluoride, for instance, incorporates ions into the tooth enamel, making it more resistant to acid attack and inhibiting the growth of bacteria that can cause caries (4). On the other hand, CPP-ACP binds to the surface of demineralised enamel and forms a protective layer that helps prevent further demineralisation and promotes remineralisation (5). SDF works by forming a silver precipitate on the tooth surface. This silver precipitate kills bacteria and inhibits demineralisation (6).
The SAP P11-4 is a protein that can mimic the natural process of remineralising dental enamel (1). It is a biomimetic peptide, meaning it is designed to imitate the structure and function of natural enamel proteins. SAP P11-4 functions by binding to the surface of demineralised enamel, which has lost minerals and weakened (1). When SAP P11-4 binds to demineralised enamel, it forms a three-dimensional network.
This network provides a support structure for depositing minerals, aiding in the remineralisation of the enamel. SAP P11-4 has also been shown to induce the production of reparative proteins, which can help repair damaged enamel. It is a non invasive treatment that can be applied to the teeth by a dentist. SAP P11-4 is still in the early stages of development, but it has the potential to revolutionise the treatment of dental caries (1). SAP P11-4 is commercially available as Curodont™ Repair, administered as a water solution using an applicator (1). It is a non invasive treatment that can be applied to the teeth by a dentist (1).
The SAP P11-4 has shown promising results in preclinical and clinical studies (7),(8),(9),(10),(11). Multiple clinical studies were conducted to compare the effects of SAP P11-4 to other remineralising agents in treating early carious enamel or WSLs (12),(13),(14),(15),(16),(17),(18),(19),(20),(21),(22),(23),(24),(25),(26). The present review focuses on the most recent studies discussing the remineralising potential of SAP P11-4 and compares it to other available remineralising agents.
Structure
SAP P11-4 is a peptide that self-assembles. It is an 11-amino acid short-chain peptide with the unique ability to self-assemble into three-dimensional fibrillar scaffolds (10),(27). Its chemical makeup, Ace-Gln-Gln-Arg-Phe-Glu-Trp-Glu-Phe-Glu-Gln-Gln-Gln-NH2, consists of 11 amino acids, enabling it to self-assemble into higher-order structures such as tapes, ribbons, fibrils, and fibers. These higher-order structures can mimic the enamel matrix structure of dental enamel (28). The 20 naturally occurring α-amino acids that make up proteins and peptides can construct the hierarchy of supramolecular structures similarly due to their intrinsic chirality. They can self-assemble to create “double tapes,” “helical tapes (single molecule thick),” “fibrils (twisted stacks of ribbons),” and fibers with increasing concentration (29). Most self-assembling molecules include both hydrophilic and hydrophobic components, making them amphiphilic. The amphiphilicity of peptides, which allows functional groups to be present on the surface of the structure, is the primary factor promoting self-assembly (29). Due to structural folding, various folded surfaces are exposed to different environmental conditions, resulting in distinct “faces.” Peptides with greater complexity and amphiphilicity are more suitable for self-assembly (29).
Synthesis: Aggeli A et al., designed a de novo 11-residue peptide, CH3CO-Gln-Gln-Arg-Phe-Gln-Trp-Gln-Phe-Glu-Gln-Gln-NH2, using criteria for designing gel-producing peptides gathered from their observations and existing literature, with the aim of creating β-sheet polymer tapes in water (30).
Glu (-CH2 CH2 COOH) or Orn (-CH2 CH2 CH2 NH2) were added to the primary structure of the 11-amino acid peptides by Aggeli A et al., demonstrating that pH adjustment can rapidly (within a matter of seconds) control self-assembly (31). The synthetic peptide P11-4 (CH3 CO-Gln-Gln-Arg-Phe-Glu-Trp-Glu-Phe-Glu-Glu-Phe-Glu Gln-Gln-NH2) forms scaffolds through hierarchical self-assembly in response to specific environmental cues and increasing peptide concentrations (18). The scaffold-like structures of self-assembled P11-4, with negatively charged domains, resemble biological macromolecules found in the extracellular matrix of mineralised tissues (32).
It has been demonstrated that the SAP P11-4 promotes the nucleation of hydroxyapatite on its surface through the resulting fibers (33). After surface treatment with SAP P11-4, two in-vitro investigations effectively demonstrated the secondary conformation of the fibrils formed on the lesion surface, specifically the pleated sheets, using a Transmission Electron Microscope (TEM) and congo red stain (18),(33).
Mechanism of action of Self-Assembling Peptide (P11-4)
Remineralising potential: The demineralised tooth surface serves as the initial stage. SAPs extend their charged amino acid side chains, 7forming electrostatic bonds with the oppositely charged mineral surface through a series of ionic interactions (32). For minerals from saliva and remineralising agents to be effective, nucleation sites, which are places for minerals to begin building up on the tooth surface, are required (27). SAPs fold their peptide chains to present a template for hydroxyapatite crystals. Specific amino acid sequences within the scaffold act as potent mineral binding sites, attracting and coordinating calcium and phosphate ions. These ions assemble into ordered lattices that mimic the complex architecture of natural enamel. The ordered structure and interactions with the mineral surface influence crystal growth, determining size and morphology with remarkable precision (32). This precise control results in the formation of smaller, densely packed crystals that faithfully replicate the natural enamel architecture and ensure seamless integration with the existing structure. Furthermore, SAPs possess the ability to inhibit enzymes such as matrix metalloproteinases, which would otherwise dissolve the enamel. This dual action, promoting remineralisation while protecting the existing structure, strengthens the tooth’s defensive barrier and promotes long-term oral health (27),(32).
Clinical Applications and Studies
Non clinical studies: Early laboratory studies from the last few decades have demonstrated that monomeric low-viscosity peptide solutions can be injected into enamel defects to stably produce scaffolds capable of nucleating hydroxyapatite, thereby promoting remineralisation (27),(32). Non clinical studies comparing the effect of SAP P11-4 to other remineralising agents are summarised in (Table/Fig 1) (12),(13),(14),(15),(16),(17),(34).
Clinical studies: The first in-vivo clinical trial of SAP P11-4, conducted by Brunton PA et al., demonstrated that a single treatment of SAP P11-4 resulted in a significant decrease in the size of early carious lesions in 15 healthy adults. After six months of observation, most lesions were found to be inactive (18). The present study led to a series of clinical trials, which are summarised in (Table/Fig 2) (3),(8),(10),(18),(19),(20),(21),(22),(23),(24),(25),(26).
Disadvantages: In a study by Brunton PA et al., two drawbacks were identified. Firstly, there was transient dental hypersensitivity, and secondly, participants showed sensitivity to the Corsodyl mouthwash provided for the study. Among the 11 adverse events recorded by Brunton PA et al., two were considered to be probably related to the study protocol (18).
In 2017, Wierichs RJ et al., discussed the limitations of the SAP method. They concluded that flocculation occurs in the nematic form of SAP in oral environmental conditions, where cycles of demineralisation and remineralisation cause pH fluctuations. The flocculated state of SAP is relatively inactive and may hinder the remineralisation process. They observed that the presence of these flocculates on the enamel surface affects the migration of calcium, phosphate, and fluoride ions during the remineralisation process. Consequently, there is reduced availability of fluoride ions in the later stages of demineralisation (19).
Self Assembling Peptide P11-4 has recently emerged in dentistry as a highly promising biomaterial for biomimetic regeneration, primarily due to its ability to mimic the extracellular matrix of enamel. Overall, it represents a groundbreaking remineralising agent that has the potential to revolutionise the treatment of dental caries. There is sufficient evidence to conclude that SAP P11-4 is more effective than other remineralising agents such as fluoride, CPP-ACP, and SDF. However, its efficacy when used alone is still considered inferior. There is a potential synergistic effect when combining SAP P11-4 with fluoride, but further investigation is recommended. More clinical trials with longer follow-up periods are necessary to establish a fair comparison, particularly in terms of short- and longterm effectiveness, efficacy in different populations, and safety.
DOI: 10.7860/JCDR/2024/68405.18881
Date of Submission: Oct 31, 2023
Date of Peer Review: Nov 23, 2023
Date of Acceptance: Dec 22, 2023
Date of Publishing: Jan 01, 2024
AUTHOR DECLARATION:
• Financial or Other Competing Interests: None
• Was Ethics Committee Approval obtained for this study? No
• Was informed consent obtained from the subjects involved in the study? No
• For any images presented appropriate consent has been obtained from the subjects. No
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ETYMOLOGY: Author Origin
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