Inducing α-helicity through side-chain cross-linking is a strategy that has been pursued to improve peptide conformational rigidity and bio-availability. Here we describe the preparation of small peptides tethered to chiral sulfoxide-containing macrocyclic rings. Furthermore, a study of structure-activity relationships (SARs) disclosed properties with respect to ring size, sulfur position, oxidation state, and stereochemistry that show a propensity to induce α-helicity. Supporting data include circular dichroism spectroscopy (CD), NMR spectroscopy, and a single crystal X-ray structure for one such stabilized peptide. Finally, theoretical studies are presented to elucidate the effect of chiral sulfoxides in inducing backbone α-helicity.
Defensins are small cationic cysteine rich peptides, which usually contain 18-45 amino acids and possess amphiphilic properties. The term "defensin" was coined as the sequences of rabbit and human leukin/phagocytin molecules were first reported in 1985. Since then, various defensins were isolated and characterized from insects, plants and vertebrates. Using vertebrate defensins as examples, defensins are categorized into three sub-families based on their different patterns of intramolecular disulfide linkages: α defensins, β defensins, and θ defensins. During the past decades, continuous attentions were casted on various defensins for their broad activity against bacteria, fungi and viruses. In this review, we focus on the effect of characteristic intramolecular disulfide bonds on the antimicrobial activity of defensins. The disulfide bonds are important for holding the defensins in their three dimensional structures, while also contribute to their antimicrobial activity and chemotactic activity. This review summarizes the effects of disulfide bonds, their synthetic formation pathways and potential pharmaceutical applications.
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