Salivary proteolysis of histidine-rich polypeptides and the antifungal activity of peptide degradation products

Xu, Ling; K, Lal; Santarpia, R. P.; Pollock, Jerry J.

doi:10.1016/0003-9969(93)90133-7

Cited by 48 publications

(43 citation statements)

References 18 publications

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“…The peptides (in this case, only Hsn-5 and MUC7 D1) were incubated with unfiltered whole saliva for 0.5 h without or with the serine protease inhibitors aprotinin and PMSF. Degradation of Hsn-5 by human saliva was previously shown to be mediated mainly by a trypsin-like enzyme activity (24). After incubation, the samples were resolved by both cationic PAGE (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…However, Hsn-5 has been shown to be very vulnerable to degradation by human saliva. This degradation was found to be mediated mainly by a trypsin-like enzyme activity, and the degraded Hsn-5 was found to be less effective in killing Candida albicans (24). In our effort to produce Hsn-5 variants with enhanced protective function and/or increased resistance to proteolysis, we produced two Hsn-5 variants fulfilling these criteria (19,20).…”

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confidence: 99%

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In Vitro Assessment of Antifungal Therapeutic Potential of Salivary Histatin-5, Two Variants of Histatin-5, and Salivary Mucin (MUC7) Domain 1

Situ

Bobek

2000

Antimicrob Agents Chemother

108

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Human salivary histatin-5 (Hsn-5) is a 24-residue peptide that possesses potent antifungal activity in vitro. The MUC7 gene encodes human salivary low-molecular-weight mucin (MG2). The candidacidal activity of MUC7 domain 1 (MUC7 D1, the N-terminal 51 amino acid residues of MUC7) in vitro has also been demonstrated. In this study, we have investigated the antifungal therapeutic potential of Hsn-5, its two variants, R12I/K17N and R12I/H21L, and MUC7 D1. First, these peptides were tested for activities against different clinically important fungi. We found them to possess broad-spectrum antifungal activities; specifically, most exhibited excellent in vitro activity against eight clinically important fungal strains tested, including Candida albicans and Candida glabrata and their azole-resistant counterparts and Cryptococcus neoformans and its amphotericin B-resistant counterpart. These findings also suggest that the mechanism of action of both Hsn-5 and MUC7 D1 for these fungi is different from that of amphotericin B or azole antifungal agents. Second, we examined the stability of these peptides in whole human saliva and human serum. In saliva, the Hsn-5 variants R12I/K17N and R12I/H21L and MUC7 D1 degraded at a lower rate than Hsn-5. In human serum, MUC7 D1 was also more stable than Hsn-5; both peptides were more stable in serum than in saliva. Third, we examined the cytotoxicity of these peptides using human erythrocytes and two human cell lines (KB and HSG). No (or very low) hemolytic activity was observed with any of the four peptides, even at the highest protein concentration tested (200 M), while amphotericin B caused 100% hemolysis at only 12.5 M. The toxic effects of Hsn-5 and MUC7 D1 toward KB and HSG cells were also much lower than that of amphotericin B as measured by trypan blue exclusion. Together, these findings indicate that the investigated peptides possess high antifungal therapeutic potential, in particular for the treatment of drug-resistant fungal strains associated with immunocompromised (particularly human immunodeficiency virus-infected) patients. The same peptides could also be used as components of artificial saliva for patients with salivary dysfunction.

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

In Vitro Assessment of Antifungal Therapeutic Potential of Salivary Histatin-5, Two Variants of Histatin-5, and Salivary Mucin (MUC7) Domain 1

Situ

Bobek

2000

Antimicrob Agents Chemother

108

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“…Two major processes are likely to account for these differences: (i) the dynamic turnover of salivary proteins balancing secretion with proteolytic degradation (64,65) and (ii) the phenomenon first described as "masking" (62) that is likely due to Hsts binding with salts and possibly with various metals, including Ca (66), Cu, and Zn in saliva. A similar phenomenon was also observed for the candidacidal activity of another antimicrobial salivary protein, lactoferrin (67).…”

Section: Hst 5 Metal Binding Abilities As a Potential Candidacidal Mementioning

confidence: 99%

How Does It Kill?: Understanding the Candidacidal Mechanism of Salivary Histatin 5

2014

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Histatins are salivary cationic peptides that provide the first line of defense against oral candidiasis caused by Candida albicans. This minireview presents a critical evaluation of our knowledge of the candidacidal mechanism of histatin 5 (Hst 5). Hst 5 is the most potent among all histatin family members with regard to its antifungal activity. The mode of action of Hst 5 has been a subject of intense debate. Unlike other classical host innate immune proteins, pore formation or membrane lysis by Hst 5 has largely been disproven, and it is now known that all targets of Hst 5 are intracellular. Hst 5 binds C. albicans cell wall proteins (Ssa1/2) and glycans and is taken up by the cells through fungal polyamine transporters in an energy-dependent manner. Once inside the fungal cells, Hst 5 may affect mitochondrial functions and cause oxidative stress; however, the ultimate cause of cell death is by volume dysregulation and ion imbalance triggered by osmotic stress. Besides these diverse targets, a novel mechanism based on the metal binding abilities of Hst 5 is discussed. Finally, translational approaches for Hst 5, based on peptide design and synergy with other known drugs, are considered a step forward for bench-to-bed application of Hst 5.

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“…Twelve HRPs, named HRP 1 to 12, have been isolated from human saliva and their primary structures determined (Troxler et al ., 1990). Additional members of this protein family have been identified (Xu et al ., 1993). The most prominent members are HRPs 1, 3, and 5, and they account for 85-90% of this family.…”

Section: (C) Histatinsmentioning

confidence: 99%

Interaction of Plant Polyphenols with Salivary Proteins

Bennick

2002

Critical Reviews in Oral Biology & Medicine

385

265

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Tannins are polyphenols that occur widespread in plant-based food. They are considered to be part of the plant defense system against environmental stressors. Tannins have a number of effects on animals, including growth-rate depression and inhibition of digestive enzymes. Tannins also have an effect on humans: They are, for example, the cause of byssinosis, a condition that is due to exposure to airborne tannin. Their biological effect is related to the great efficiency by which tannins precipitate proteins, an interaction that occurs by hydrophobic forces and hydrogen bonding. Two groups of salivary proteins, proline-rich proteins and histatins, are highly effective precipitators of tannin, and there is evidence that at least proline-rich proteins act as a first line of defense against tannins, perhaps by precipitating tannins in food and preventing their absorption from the alimentary canal. Proline plays an important role in the interaction of proline-rich proteins with tannins. In contrast, it is primarily basic residues that are responsible for the binding of histatins to tannin. The high concentration of tannin-binding proteins in human saliva may be related to the fruit and vegetable diet of human ancestors.

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Salivary proteolysis of histidine-rich polypeptides and the antifungal activity of peptide degradation products

Cited by 48 publications

References 18 publications

In Vitro Assessment of Antifungal Therapeutic Potential of Salivary Histatin-5, Two Variants of Histatin-5, and Salivary Mucin (MUC7) Domain 1

In Vitro Assessment of Antifungal Therapeutic Potential of Salivary Histatin-5, Two Variants of Histatin-5, and Salivary Mucin (MUC7) Domain 1

How Does It Kill?: Understanding the Candidacidal Mechanism of Salivary Histatin 5

Interaction of Plant Polyphenols with Salivary Proteins

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