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Open AccessReview

The Potential of the Cyclotide Scaffold for Drug Development

1
Department of Pharmacology and Pharmaceutical Sciences, University of Southern California, CA 9033, USA
2
Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, Los Angeles, CA 9033, USA
*
Author to whom correspondence should be addressed.
Biomedicines 2019, 7(2), 31; https://doi.org/10.3390/biomedicines7020031
Received: 6 April 2019 / Revised: 13 April 2019 / Accepted: 15 April 2019 / Published: 19 April 2019
(This article belongs to the Special Issue Discovery and Development of Constrained Peptide Ligands)
Cyclotides are a novel class of micro-proteins (≈30–40 residues long) with a unique topology containing a head-to-tail cyclized backbone structure further stabilized by three disulfide bonds that form a cystine knot. This unique molecular framework makes them exceptionally stable to physical, chemical, and biological degradation compared to linear peptides of similar size. The cyclotides are also highly tolerant to sequence variability, aside from the conserved residues forming the cystine knot, and are orally bioavailable and able to cross cellular membranes to modulate intracellular protein–protein interactions (PPIs), both in vitro and in vivo. These unique properties make them ideal scaffolds for many biotechnological applications, including drug discovery. This review provides an overview of the properties of cyclotides and their potential for the development of novel peptide-based therapeutics. The selective disruption of PPIs still remains a very challenging task, as the interacting surfaces are relatively large and flat. The use of the cell-permeable highly constrained polypeptide molecular frameworks, such as the cyclotide scaffold, has shown great promise, as it provides unique pharmacological properties. The use of molecular techniques, such as epitope grafting, and molecular evolution have shown to be highly effective for the selection of bioactive cyclotides. However, despite successes in employing cyclotides to target PPIs, some of the challenges to move them into the clinic still remain. View Full-Text
Keywords: cyclotides; CCK; cystine-knot; drug design; backbone cyclized polypeptides; protein-protein interactions; cyclic peptides cyclotides; CCK; cystine-knot; drug design; backbone cyclized polypeptides; protein-protein interactions; cyclic peptides
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MDPI and ACS Style

Camarero, J.A.; Campbell, M.J. The Potential of the Cyclotide Scaffold for Drug Development. Biomedicines 2019, 7, 31.

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