Abstract
Cystine-knot peptides display exceptional structural, thermal, and biological stability. Their eponymous motif consists of six cysteine residues that form three disulfide bonds, resulting in a notably rigid structural core. Since they highly tolerate either rational or combinatorial changes in their primary structure, cystine knots are considered to be promising frameworks for the development of peptide-based pharmaceuticals. Despite their relatively small size (two to three dozens amino acid residues), the chemical synthesis route is challenging since it involves critical steps such as head-to-tail cyclization and oxidative folding towards the respective bioactive isomer. Herein we describe the topology of cystine-knot peptides, their synthetic availability and briefly discuss potential applications of engineered variants in diagnostics and therapy.
Highlights
Cystine-knot peptides, termed knottins, are promising scaffolds for the design of peptide-based pharmaceuticals as they combine potent bioactivities with remarkable thermal and proteolyticMolecules 2012, 17 stabilities [1,2,3]
Cystine-knot peptides can be divided into three major subclasses: inhibitor cystine knots (ICK), cyclic cystine knots (CCK) and growth factor cystine knots (GFCK)
This moiety induces a twist in the orientation of the central β-sheet of Möbius CCK peptides, causing their oblate shape compared to bracelet cyclotides which lack this conformationally determinative unit [5]
Summary
Cystine-knot peptides, termed knottins, are promising scaffolds for the design of peptide-based pharmaceuticals as they combine potent bioactivities with remarkable thermal and proteolytic. Compared to ICK and CCK, GFCK peptides are larger, less stable and commonly produced recombinantly. Cystine-knot peptides have been found in diverse organisms: arthropoda, fungi, mollusca, plantae, porifera, and vertebrata [9,10]. Due to their wide-spread occurrence in combination with a structurally conserved core and an astonishing diversity with respect to amino acid sequence and function, they can be considered as one of Nature’s combinatorial libraries [11]
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