STRUCTURE-ACTIVITY STUDIES ON MAGAININS AND OTHER HOST-DEFENSE PEPTIDES

Host defense peptides are widely, distributed in nature, being found i n species fr om bacteria to humans. The structures of these peptides f rom insects, horseshoe crabs, frogs, and mammals are known to have the common features of a net cationic charge due to the presence of multi ple Arg and Lps residues and in most cases the ability to form amphipa thic structures. These properties are important for the mechanism of a ction that is thought to be a nonreceptor-mediated interaction with th e anionic phospholipids of the target cell followed by incorporation i nto the membrane and disruption of the membrane structure. Host defens e peptides have been shown to have broad spectrum antimicrobial activi ty, able to kill most strains of bacteria as well as some fungi, proto zoa, and in addition, many types of tumor cells. Specificity for patho genic cells over host cells is thought to be due to the composition of the cell membranes, with an increased proportion of anionic phospholi pids making the pathogen more susceptible and the presence of choleste rol making the host membranes more resistant. Structure-activity relat ionship studies have been performed on insect cecropins and apidaecins , horseshoe crab tachyplesins and polyphemusins, and the frog magainin s, CPFs (caerulein precursor fragments) and PGLa. In general, changes that increased the basicity, and stabilized the amphipathic structure have increased the antimicrobial activity; however, as the peptides be come more hydrophobic the degree of specificity decreases. One magaini n-2 analogue, MSI-78, has been developed by Magainin Pharmaceuticals a s a topical antiinfective and is presently in clinical trials for the treatment of infected diabetic food ulcers. (C) 1995 John Wiley & Sons , Inc.