Host defense peptides are widely distributed in nature, being found in species from bacteria to humans. The structures of these
peptides from insects, horseshoe crabs, frogs, and mammals are known to have the common features of a net cationic charge due to the presence of multiple Arg and Lys residues and in most cases the ability to form amphipathic structures. These properties are important for the mechanism of action that is thought to be a nonreceptor-mediated interaction with the anionic
phospholipids of the target cell followed by incorporation into the membrane and disruption of the membrane structure.
Host defense peptides have been shown to have broad spectrum antimicrobial activity, able to kill most strains of bacteria as well as some fungi, protozoa, and in addition, many types of
tumor cells. Specificity for pathogenic cells over host cells is thought to be due to the composition of the cell membranes, with an increased proportion of anionic
phospholipids making the pathogen more susceptible and the presence of
cholesterol making the host membranes more resistant. Structure-activity relationship studies have been performed on insect
cecropins and apidaecins, horseshoe crab tachyplesins and polyphemusins, and the frog
magainins, 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 become more hydrophobic the degree of specificity decreases. One magainin-2 analogue,
MSI-78, has been developed by
Magainin Pharmaceuticals as a topical antiinfective and is presently in clinical trials for the treatment of infected
diabetic foot ulcers.