Reconstruction of the Conserved β-Bulge in Mammalian Defensins Using d-Amino Acids

Human α-defensins block papillomavirus infection

“…The ability of defensins to disrupt membranes is thought to depend, at least in part, on charge-charge interactions between the cationic defensin and anionic lipid headgroups. A recent study of HNP-2 mutants with altered overall charges showed that various mutants displayed dramatic changes in antibacterial activity and altered ability to interact with synthetic membranes (22). We examined the ability of these mutants to antagonize HPV16 PsV transduction and found that, in contrast to their altered antibacterial effects, these mutants all retained similar anti-HPV effects ( Table 2).…”

“…Because defensins are known to interact with membranes, it is possible to imagine that they act against papillomaviruses and adenoviruses by interacting with cellular membranes in a manner that blocks the effects of membrane-destabilizing viral peptides. To begin to address this question, we performed a series of experiments involving a previously described panel of HNP-2 mutant peptides (22). Although the various mutant peptides have altered ability to bind synthetic membranes and to disrupt bacteria, none of the mutations had a major effect on inhibition of HPV16 PsV ( Table 2).…”

“…Compounds were purchased from commercial suppliers, as listed in Table 1, or synthesized and folded according to procedures reported in refs. [20][21][22]. Compounds were dissolved in water, typically at 1 mg͞ml.…”

Functional Determinants of Human Enteric α-Defensin HD5

“…Many of the prior studies have been focused on two model systems: HNP1 and ␣-defensins from mouse crypts, also known as cryptdins (50). Collectively, these studies have provided important insights into the structural and functional roles of disulfide bonding (51,52), cationicity (53,54), and conserved elements, such as the Arg-Glu salt bridge (55)(56)(57)(58) and invariant Gly residue (59,60) in the action of ␣-defensins. Recently, a comprehensive Ala scanning mutagenesis of HNP1 has discovered that a hydrophobic residue near the C terminus, Trp 26 , governs the ability of this ␣-defensin to kill Staphylococcus aureus, inhibit anthrax lethal factor, and bind HIV-1 envelope glycoprotein gp120 (61); methylation of a peptide bond at the putative dimer interface of HNP1 debilitates its dimerization and is functionally detrimental (62).…”

“…E21I-HD5 was also synthesized by this procedure. All of the cysteine residues (Cys 3 (59,60), two residues that form a structurally essential salt bridge (Arg 6 and Glu…”