Abstract
θ-Defensins are ribosomally synthesized cyclic peptides found in the leukocytes of some primate species and have promising applications as antimicrobial agents and scaffolds for peptide drugs. The cyclic cystine ladder motif, comprising a cyclic peptide backbone and three parallel disulfide bonds, is characteristic of θ-defensins. In this study, we explore the role of the cyclic peptide backbone and cystine ladder in the structure, stability, and activity of θ-defensins. θ-Defensin analogues with different numbers and combinations of disulfide bonds were synthesized and characterized in terms of their NMR solution structures, serum and thermal stabilities, and their antibacterial and membrane-binding activities. Whereas the structures and stabilities of the peptides were primarily dependent on the number and position of the disulfide bonds, their antibacterial and membrane-binding properties were dependent on the cyclic backbone. The results provide insights into the mechanism of action of θ-defensins and illustrate the potential of θ-defensin analogues as scaffolds for peptide drug design.
Highlights
-Defensins are ribosomally synthesized cyclic peptides found in the leukocytes of some primate species and have promising applications as antimicrobial agents and scaffolds for peptide drugs
We explore the role of the cyclic peptide backbone and cystine ladder in the structure, stability, and activity of -defensins. -Defensin analogues with different numbers and combinations of disulfide bonds were synthesized and characterized in terms of their NMR solution structures, serum and thermal stabilities, and their antibacterial and membrane-binding activities
The three-disulfide mutant [Aba3,5,7,12,14,16]BTD-2 was cyclized using a peptide coupling reaction with HBTU and diisopropylethylamine in dimethylformamide [1], but the yield of cyclic peptide was lower than that of the peptides cyclized by native chemical ligation
Summary
-Defensins are ribosomally synthesized cyclic peptides found in the leukocytes of some primate species and have promising applications as antimicrobial agents and scaffolds for peptide drugs. We explore the role of the cyclic peptide backbone and cystine ladder in the structure, stability, and activity of -defensins. -Defensin analogues with different numbers and combinations of disulfide bonds were synthesized and characterized in terms of their NMR solution structures, serum and thermal stabilities, and their antibacterial and membrane-binding activities. -Defensins were first isolated from the leukocytes of rhesus macaques [1] and are currently the only backbone-cyclic peptides known in animals [2] These 18-residue peptides display antifungal, antibacterial, and antiviral activities and are thought to have an important role in the innate immunity of the prima-. The characteristic structural feature of -defensins is the cyclic cystine ladder, comprising a head-to-tail cyclic peptide backbone and three parallel disulfide bonds (Fig. 1a) [8].
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