θ-defensins:: Cyclic antimicrobial peptides produced by binary ligation of truncated α-defensins

The first cyclic peptide discovered in animals is an antimicrobial octadecapeptide that is expressed in leukocytes of rhesus monkeys. The peptide, termed rhesus theta-defensin 1 (RTD-1) is the prototype of a new family of antimicrobial peptides, which like the previously characterized alpha- and beta-defensin families, possesses broad spectrum microbicidal activities against bacteria, fungi, and protects mononuclear cells from infection by HIV-1. The cyclic theta-defensin structure is essential for a number of its antimicrobial properties, as demonstrated by the markedly reduced microbicidal activities of de-cyclized theta-defensin analogs. Genetic and biochemical experiments disclosed that the biosynthesis of RTD-1 results from the head-to-tail joining of two nine-amino acid peptides, each of which is donated by a separate precursor polypeptide, which are in fact C-terminally truncated pro-alpha-defensins. Alternate combinations of the two nonapeptides generate two additional macaque theta-defensins, RTD-2 and RTD-3. Humans do not express theta-defensin peptides, but mRNAs encoding at least two theta-defensins are expressed in human bone marrow. However, in each case the open reading frame is interrupted by a stop codon in the signal peptide-coding region. The mature theta-defensin peptide is a two-stranded beta-sheet that, like the alpha- and beta-defensins, is stabilized by three disulfides. However, the parallel orientation of the theta-defensin disulfide arrangement allows for substantial flexibility around its short axis. Unlike alpha- and beta-defensins, RTD-1 lacks an amphiphilic topology. This may partially explain the unusual interaction between theta-defensins and phospholipid bilayers.