Minidefensins: Antimicrobial Peptides with Activity Against HIV-1

Over 80 different alpha-defensin or beta-defensin peptides are expressed by the leukocytes and epithelial cells of birds and mammals. Although their broad spectrum antimicrobial properties makes them candidates for therapeutic development, technical limitations related to their size (typically 30-45 residues) and complex structure have impeded such development. The minidefensins covered in this review are antimicrobial peptides with 16-18 residues, approximately half the number found in alpha-defensins. The theta-defensins are evolutionarily related toalpha- and beta-defensins, but other minidefensins probably arose independently. Like alpha- or beta-defensins, minidefensin molecules have a net positive charge and a largely beta-sheet structure that is stabilized by intramolecular disulfide bonds. Whereas alpha-defensins are found only in mammals and theta-defensins only in nonhuman primates, the other minidefensins come from widely divergent species, including horseshoe crabs, spiders, and pigs. Several alpha-defensins and minidefensins are effective inhibitors of HIV-1 infection in vitro, and recent evidence implicates alpha-defensins in resistance to HIV-1 progression in vivo. This review compares defensins and minidefensins with respect to their activity against HIV-1. It pays special attention to retrocyclins - the ancestral theta-defensins of humans, and their extant counterparts in rhesus monkeys. In addition to describing critical elements of their structure and unusual mode of formation, we will venture some predictions about using theta-defensins as antiviral agents.