Factors contributing to the potency of antimicrobial cationic peptides from the N-terminal region of human lactoferrin.

This study investigated the antimicrobial activities of peptides derived from the N-terminal region of human lactoferrin, and examined the contributions of individual residues to the activity of the most potent peptide. Two regions of antimicrobial activity were identified, the first corresponding to a weakly active peptide, HLP-9, comprising residues 1-9, and a second corresponding to a more potent peptide, HLP-10, comprising residues 18-26 and containing the hexapeptide motif, FQWQRN. Inhibitory studies on peptides from the first region confirm the importance of tryptophan residues in enhancing and broadening peptide activity. Inhibitory studies with glycine-substituted homologues of the more potent peptide showed that F21/G and R25/G substitutions resulted in a major reduction or complete loss of activity, while increased peptide cationicity or flexibility had little effect. Our findings demonstrate that F21 and R25 are critical determinants of potency for HLP-10, and that the second aromatic residue may act synergistically with W23 in developing and enhancing the activity of this cationic peptide.

Lactoferrin reduces methotrexate-induced small intestinal damage, possibly through inhibition of GLP-2-mediated epithelial cell proliferation.

A strategy protecting the small intestine against deleterious side effects associated with anti-cancer therapy is arresting epithelial cell cycling temporally. Since endogenous glucagon-like peptide-2 (GLP-2) is a trophic factor specific for intestinal epithelia, the possibility of inhibiting GLP-2-mediated cell proliferation by lactoferrin, thereby protecting the small intestine against deleterious side effects of anticancer therapy, was investigated. In Caco-2 cells, GLP-2-mediated proliferation was reduced in a dose-dependent manner using lactoferrin. Furthermore, in a rat model for methotrexate-induced mucositis, lactoferrin reduced BrdU incorporation in small intestinal epithelial cells, indicating inhibition of epithelial cell proliferation in vivo. Subsequently, protection against methotrexate-induced intestinal damage was found in corresponding regions. These results show, for the first time, that lactoferrin interferes with GLP-2-induced intestinal epithelial proliferation. It may therefore be hypothesized that lactoferrin protects the intestine against anticancer therapy-induced intestinal damage, via inhibition of GLP-2-induced small intestinal epithelial cell proliferation.

Design and fungicidal activity of mucoadhesive lactoferrin tablets for the treatment of oropharyngeal candidosis.

Lactoferrin (Lf) is a potential drug candidate for the treatment of oropharyngeal Candida infections. However, for an effective therapeutic treatment an appropriate dosage form is required. Therefore a mucoadhesive tablet for buccal application was developed. Tablets of sufficient strength could be produced on high speed tabletting machines, but they could only be obtained when the protein contained at least 7% moisture. The tablet contained sodium alginate both for its release-controlling properties as well as for its mucoadhesive properties. Furthermore, phosphate buffer was added to keep the pH of the saliva in the mouth within the range of 6.5 to 7.5. In this pH range, Lf has shown to have its highest activity against Candida growth inhibition. The tablet formulation containing Lf had the same antifungal properties as compared with Lf alone, because in most cases identical inhibitory concentrations were observed against several clinical isolates of Candida albicans and Candida glabrata. In human volunteers the tablets, containing 250 mg Lf and placed in each pouch, were able to keep the Lf concentration in the saliva at effective levels for at least 2 hr, while the pH of the saliva remained within the desired range. We concluded that the developed mucoadhesive tablet can improve the therapeutic efficacy of Lf and that it is suitable for further clinical research.