NOVEL MAGAIN DRUGS FOR PSEUDOMEMBRANOUS COLITIS

THE LONG-RANGE OBJECTIVES OF THIS PROJECT ARE TO (1) IDENTIFY NOVEL DRUG CANDIDATES RELATED TO THE MAGAININ CLASSOF PEPTIDES WITH POTENTIAL ANTIBACTERIAL, ANTIVIRAL, AND ANTI-INFLAMMATORY ACTIVITY THAT HAVE GASTROINTESTINAL (GI)-RELATED APPLICATIONS; AND (2) ADVANCE KNOWLEDGE OF THE ROLE AND MECHANISMS OF ENDOGENOUS MEMBRANE CHANNEL-FORMING PEPTIDES. THE MAGAININS, 21 TO 27 AMINO ACID PEPTIDES ISOLATED FROM FROG SKIN, WITH REMARKABLE ANTIBACTERIAL, ANTIFUNGAL, AND ANTIPARASITIC ACTIVITIES HAVE BEEN DESCRIBED. THESE BIOLOGICALLY ACTIVE PEPTIDES ARE A NOVEL VERTEBRATE HOST DEFENSE SYSTEM, ACTING BY MEMBRANE ION CHANNEL-FORMING MECHANISMS. NEW IMMUNOLOGICAL EVIDENCE SUGGESTS THAT THE MAGAININS ARE WIDELY PRESENT IN THE FROG'S GI TRACT, POINTING TO THEIR ROLE IN GI FUNCTION AND THE POTENTIAL OF NOVEL GI THERAPEUTICS. THE SPECIFIC AIM IS TO MAP THE MAMMALIAN GI TRACT FOR MAGAININ-LIKE PEPTIDES. ANTIBODIES TO SPECIFIC PEPTIDES TO DETECT STRUCTURALLY RELATED MOLECULES AND SENSITIVE ANTIMICROBIAL BIOASSAYS TO GUIDE PURIFICATION AND AID IN THEDISCOVERY OF NOVEL MOLECULES WILL BE USED. ISOLATED PEPTIDES WILL BE SEQUENCED AND SYNTHETIC PEPTIDES MADE TO CONFIRM AUTHENTICITY; BIOLOGICAL TESTING WILL BE EXPANDED. THESE STUDIES CAN LEAD TO MAJOR ADVANCES IN UNDERSTANDING MAGAININ COMPOUNDS AND HOST DEFENSES AND OPEN NEW APPROACHES TO GI THERAPEUTICS.