title: Novel molecules for intra-oral delivery of antimicrobials to prevent and treat oral infectious diseases.
abstract: New molecules were designed for efficient intra-oral delivery of antimicrobials to prevent and treat oral infection. The salivary statherin fragment, which has high affinity for the tooth enamel, was used as a carrier peptide. This was linked through the side chain of the N-terminal residue to the C-terminus of a defensin-like 12-residue peptide to generate two bifunctional hybrid molecules, one with an ester linkage and the other with an anhydride bond between the carrier and the antimicrobial components. They were examined for their affinity to a HAP (hydroxyapatite) surface. The extent of the antimicrobial release in human whole saliva was determined using 13C-NMR spectroscopy. The candidacidal activity of the molecules was determined as a function of the antimicrobial release from the carrier peptide in human saliva. The hybrid-adsorbed HAP surface was examined against Candida albicans and Aggregatibacter actinomycetemcomitans using the fluorescence technique. The bifunctional molecules were tested on human erythrocytes, GECs (gingival epithelial cells) and GFCs (gingival fibroblast cells) for cytotoxicity. They were found to possess high affinity for the HAP mineral. In human whole saliva, a sustained antimicrobial release over a period of more than 40-60 h, and candidacidal activity consistent with the extent of hybrid dissociation were observed. Moreover, the bifunctional peptide-bound HAP surface was found to exhibit antimicrobial activity when suspended in clarified human saliva. The hybrid peptides did not show any toxic influence on human erythrocytes, GECs and GFCs. These novel hybrids could be safely used to deliver therapeutic agents intra-orally for the treatment and prevention of oral infectious diseases.
authors.affiliation: Perident Therapeutics, Inc., 7912 West Burdick Avenue, Milwaukee, WI 53219, USA. paraj@perident.net
authors.forename: Periathamby Antony
authors.initials: PA
authors.lastname: Raj
authors.forename: Latha
authors.initials: L
authors.lastname: Rajkumar
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Dentino
mesh_terms: D000284:Administration, Oral; D000595:Amino Acid Sequence; D000890:Anti-Infective Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology; D002176:Candida albicans / Q000187:drug effects; D002942:Circular Dichroism; D023082:Defensins / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology; D004337:Drug Carriers / Q000138:chemical synthesis / Q000737:chemistry*; D005882:Gingival Diseases / Q000188:drug therapy / Q000517:prevention & control; D006801:Humans; D017053:Infection Control; D007239:Infections / Q000188:drug therapy; D007700:Kinetics; D008969:Molecular Sequence Data; D015661:Pasteurellaceae / Q000187:drug effects; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D010510:Periodontal Diseases / Q000188:drug therapy* / Q000382:microbiology / Q000517:prevention & control; D012463:Saliva / Q000382:microbiology; D012471:Salivary Proteins and Peptides / Q000737:chemistry*
chemical_list: D000890:Anti-Infective Agents; D023082:Defensins; D004337:Drug Carriers; D010455:Peptides; D012471:Salivary Proteins and Peptides; C526443:arginyl-leucyl-cysteinyl-arginyl-isoleucyl-valyl-valyl-isoleucyl-arginyl-valyl-cysteinyl-arginyl-aspartyl-aspartyl-aspartyl-aspartyl-glutamyl-glutamic acid (3-11)disulfide; C526442:arginyl-leucyl-cysteinyl-arginyl-isoleucyl-valyl-valyl-isoleucyl-arginyl-valyl-cysteinyl-arginyl-seryl-aspartyl-aspartyl-aspartyl-glutamyl-glutamic acid (3-11)disulfide