Exploring the Healing Powers of Histatins: From Oral Health to Therapeutics
Abstract
1. Introduction
2. Gene Expression and Transcriptional Regulation
3. Post-Translational Modifications
4. Structure and Functional Domains of Histatins
5. Domain-Specific Functions
5.1. Antifungal Properties
5.2. Antibacterial Properties
5.3. Enamel Fortification
5.4. Immunomodulation
5.5. Wound Healing
5.6. Possible Role in Cancer
6. Biomedical Applications of Histatins
6.1. Histatins as Biomarkers
6.2. Histatins as Therapeutic Peptides
6.2.1. Antimicrobial Therapy
6.2.2. Caries Prevention Therapy
6.2.3. Tissue Bioengineering
6.2.4. Anticancer Therapy
7. Overcoming Limitations in Therapeutic Applications of Histatins
7.1. Combined Histatin Preparations for Enhanced Functionality
7.2. Overcoming Proteolytic Instability
7.3. Achieving Gradual and Constant Release of Histatins
7.4. Improving Histatin Delivery in Therapeutics
7.5. Modifying Peptide Length to Ensure Best Possible Drug Efficiency
8. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Histatin Type | Disease Name | References |
---|---|---|
Histatin-1 | Type I diabetes | [110] |
Histatin-1 | Periodontal disease | [111] |
Histatin-1 | AIDS | [112,113] |
Histatin-5 | Caries | [114,115] |
Histatin-3 or Histatin-5 | Alzheimer’s disease | [116] |
Histatin-5 | Stress | [117] |
Histatin-2 | Addictions including cocaine | [118,119] |
Histatin-3 | Obesity in pregnancy with periodontitis | [120] |
Histatin-1 | Bone diseases | [121] |
Histatin-1 | Aqueous-deficient dry eye disease (ADDE) | [122] |
Histatin-3 | Oral squamous cell carcinoma | [109] |
Name | Modification/ Engineering | Purpose/ Applications | References |
---|---|---|---|
Repeat-histatin-3 Repeat-histatin-3-repeat | Functional domain was repeated in tandem | 5 times increased candidacidal activity | [148] |
DR9-RR14 | Hybrid of histatin-3 with statherin | Inhibit enamel demineralisation | [149] |
Three histatin-5 proline variants 1:H21P 2:H19P/H21P 3:E16P/H19P/H21P | One or more residues were replaced with proline (potent α-helix breaker) | α-helix may not be important for candidacidal activity of histatin-5 | [37] |
ATCUN-C16 (modified histatin-5) | Contains two metal-binding centres, ATCUN motif (Cu-binding) and a Zn-binding motif | Assumes a more stable conformation and possesses nuclease activity, making it a suitable candidate for anticancer treatment and a biotechnological tool | [12] |
Dhvar2 and modified dhvar2 (L7F) (modified histatin-5) | L7F (KRLFKEFLFSLRKY), required to facilitate peptide self-assembly into ordered nanostructures | Antimicrobial peptides with the ability to self-assemble into ordered amyloid-like nanostructures, facilitating their antibacterial activity and stable antifungal activities | [150] |
P-113 Histatin-5 (C-terminal modification) | 12-amino-acid sequence amidated on C terminus, reducing propensity to make an α-helix | Two-fold increase in fungicidal activity after amidation. LD50 = 2.3 ± 0.65 µg/mL | [49] |
Histatin-5 (K17R) | Lysine at position 17 substituted for arginine in histatin-5 | Confers increased resistance to proteolysis by Saps | [151] |
Histatin-5 (K17L) | Lysine at position 17 substituted for leucine in histatin-5 | Enhanced antifungal activity | [151] |
Histatin-5 (K11R) | Lysine at position 11 substituted for arginine | Enhanced antifungal activity | [151] |
W-histatin-5 | Tryptophan (W) added in histatin-5 sequence | Prolonged fungicidal activity | [145] |
Patents of histatin-5 and derivatives | |||
Cyclic analogues of histatin-5 U.S. Patent. 2011 November 10 (US 2014/0065119A1) | The invention focuses on the use of cyclic analogues of histatin-5 for the treatment of wounds. Cyclable amino acids can be incorporated to induce cyclisation in histatin-5 and its derivatives. | Cyclisation improves stability and cellular uptake of histatin-5. Therapeutically effective doses range from 0.01 mg to 100 mg per kg of body weight. A suitable absorbent hydrogel can be developed for topical application. Histatin-5, along with other therapeutic agents, can be used for wound healing. | [152,153] |
WO 2016/060916 A1 | The invention focuses on the utilisation of combined histatin-5 and histatin-1 as therapeutic agents for ocular surface diseases such as dry eyes. | Histatin-5, being a modulator of inflammatory cytokines, can be incorporated in anti-inflammatory formulations along with other therapeutics. The preferred weight-to-weight ratios of histatin-5 to cHistatin-1 were 1:1, 6:1, 1:10, and 1:15. Histatin-5 and histatin-1 were combined in ranges from 1 μg to 10 mg/mL. Both histatins were mixed with 0.1% to 1% glycerin to form sterile eye drops. Histatin-5, along with rapamycin, can be administered to treat dry eyes in patients suffering from autoimmune diseases such as Sjogren’s syndrome. | [152,154] |
US 7781531 B2 | Dentures conventionally made from poly (methyl methacrylate) lead to denture-induced stomatitis in the user due to adhesion of C. albicans. | This invention focuses on the incorporation of histatin-5 with phosphate-containing co-polymers in dentures. Phosphate anions facilitate the adhesion of cationic histatin molecule overdentures to limit the induced complications. Adsorption of histatin-5 increases with an increase in the negative charge on the polymer. | [152,155] |
WO 2009/005798 A2 | The invention is a histatin-5 derivative-based mouth rinse formulation with improved antifungal activity. | Amidation at the carboxyl terminus of the histatin-5 derivative resulted in a two-fold increase in antimicrobial activity. | [152,156] |
US 2010/0202983 A1 | The invention describes the utilisation of carrier agents for the delivery of histatins and their derivatives for the treatment of periodontal disease. | Carrier agents and histatins are covalently coupled to form a complex. The formed complex ensures sustained release of histatins with better penetration and retention. | [152,157] |
Name | Modification | Application | Reference |
---|---|---|---|
M21 (modified histatin-5) | K13T | Reduced fungicidal activity | [22] |
M71 (modified histatin-5) | K13E | Reduced fungicidal activity | [22] |
Dhvar2 (modified histatin-5) | Increased HIV-1 replication by promoting the envelope-mediated cell entry process | Modification of antimicrobial peptides in order to improve their activity against a pathogen may have unpredictable and unwanted side effects on other pathogens | [158] |
LL37 and melittin (modified histatin-5) | Enhanced antifungal activity with increased growth of Lactobacillus species | Unwanted side effects on other commensals | [147] |
Histatin-5— Histatin-5; Histatin-5—C16, C16—C16) | More potent histatin-5 molecules may be achieved by duplication of the functional domain of histatin-5 (C16, residues 9–24 of histatin-5) | Decreased candidacidal activity | [159] |
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Usman, S.; You, Y.; Waseem, A. Exploring the Healing Powers of Histatins: From Oral Health to Therapeutics. Int. J. Mol. Sci. 2025, 26, 5019. https://doi.org/10.3390/ijms26115019
Usman S, You Y, Waseem A. Exploring the Healing Powers of Histatins: From Oral Health to Therapeutics. International Journal of Molecular Sciences. 2025; 26(11):5019. https://doi.org/10.3390/ijms26115019
Chicago/Turabian StyleUsman, Saima, Yvonne You, and Ahmad Waseem. 2025. "Exploring the Healing Powers of Histatins: From Oral Health to Therapeutics" International Journal of Molecular Sciences 26, no. 11: 5019. https://doi.org/10.3390/ijms26115019
APA StyleUsman, S., You, Y., & Waseem, A. (2025). Exploring the Healing Powers of Histatins: From Oral Health to Therapeutics. International Journal of Molecular Sciences, 26(11), 5019. https://doi.org/10.3390/ijms26115019