MAGAININS' ROLE IN INHIBITING ORAL FLORA AND SYNERGY EFFECTS

THE LONG-TERM OBJECTIVES OF THIS PROJECT ARE TO (1) IDENTIFYNOVEL DRUG CANDIDATES RELATED TO THE MAGAININ PEPTIDE CLASS WITH POWERFUL ANTI-INFECTIVE ACTIVITY AGAINST PATHOGENIC ORAL CAVITY FLORA, (2) USE IN VIVO MODELS TO TEST MAGAININS'ROLE IN PREVENTING AND/OR TREATING ROOT SURFACE CARIES AND PERIODONTAL DISEASES, AND (3) DETERMINE MAGAININ EFFICACY ASA PROPHYLACTIC AND/OR TREATMENT INTERVENTION OF THE ORAL CAVITY TO REDUCE THE INCIDENCE OF SYSTEMIC COMPLICATIONS IN IMMUNOCOMPROMISED PATIENTS. MAGAININS, 21- TO 27-AMINO ACID PEPTIDES ISOLATED FROM FROG SKIN, HAVE REMARKABLE ANTIBACTERIAL, ANTIFUNGAL, AND ANTIPARASITIC ACTIVITIES. THESE PEPTIDES ARE A NOVEL VERTEBRATE HOST DEFENSE SYSTEM, ACTING BY MEMBRANE ION CHANNEL-FORMING MECHANISMS. IMMUNOHISTOCHEMICAL AND WESTERN BLOT EXPERIMENTS SUGGEST MAGAININ-LIKE PEPTIDES MAY BE PRESENT IN HUMAN SALIVA AND SALIVARY GLANDS AND FUNCTION ENDOGENOUSLY IN CONTAINING ORAL FLORA. THE SPECIFIC AIMS ARE TO (1) DETERMINE MAGAININ EFFECTS ON IMPORTANT ORAL BACTERIA, (2) DETERMINE DOSE-RESPONSE AND STRUCTURE-ACTIVITY RELATIONSHIPS OF NEW IMPROVED MAGAININ DERIVATIVES, (3) PRODUCE ANALOGS THAT RESIST BREAKDOWN BY ORAL PEPTIDASES THROUGH AMINO ACID SUBSTITUTIONS, AND (4) DETERMINE IF MAGAININS EXHIBIT THERAPEUTIC SYNERGISM AGAINST IMPORTANT ORAL FLORA WITH FLUORIDE AND OTHER ANTI-INFECTIVES.