Minidefensins: Antimicrobial Peptides with Activity Against HIV-1

Over 80 different α-defensin or β-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 α-defensins. The θ-defensins are evolutionarily related to α- and β-defensins, but other minidefensins probably arose independently. Like α- or β-defensins, minidefensin molecules have a net positive charge and a largely betα-sheet structure that is stabilized by intramolecular disulfide bonds. Whereas α-defensins are found only in mammals and θ-defensins only in nonhuman primates, the other minidefensins come from widely divergent species, including horseshoe crabs, spiders, and pigs. Several α-defensins and minidefensins are effective inhibitors of HIV-1 infection in vitro, and recent evidence implicates α-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 θ-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 θ-defensins as antiviral agents.