Cyclotides, A Promising Molecular Scaffold for Peptide-Based Therapeutics

Department of Pharmacology and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA 90033, USA.
Biopolymers (Impact Factor: 2.39). 05/2010; 94(5):611-6. DOI: 10.1002/bip.21433
Source: PubMed


Cyclotides are a new emerging family of large plant-derived backbone-cyclized polypeptides (≈30 amino acids long) that share a disulfide-stabilized core (three disulfide bonds) characterized by an unusual knotted structure. Their unique circular backbone topology and knotted arrangement of three disulfide bonds make them exceptionally stable to thermal, chemical, and enzymatic degradation compared to other peptides of similar size. Currently, more than 100 sequences of different cyclotides have been characterized, and the number is expected to increase dramatically in the coming years. Considering their stability and biological activities like anti-HIV, uterotonic, and insecticidal, and also their abilities to cross the cell membrane, cyclotides can be exploited to develop new stable peptide-based drugs. We have recently demonstrated the intriguing possibility of producing libraries of cyclotides inside living bacterial cells. This opens the possibility to generate large genetically encoded libraries of cyclotides that can then be screened inside the cell for selecting particular biological activities in a high-throughput fashion. The present minireview reports the efforts carried out toward the selection of cyclotide-based compounds with specific biological activities for drug design. © 2010 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 94: 611–616, 2010.
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    • "Despite possessing identical topology to Mö bius and bracelet cyclotides, members of the trypsin inhibitor subfamily lack hydrophobic residues (Felizmenio-Quimio et al., 2001), have exquisite trypsin inhibitory activity and low cytotoxicity (Hernandez et al., 2000), and have been found exclusively in cucurbitaceous plant species (Mahatmanto et al., 2015). The application of cyclotides as drug leads (Henriques and Craik, 2010; Jagadish and Camarero, 2010) was originally motivated by their remarkable stability, diverse biological activities, sequence variability, and amenability to chemical synthesis (Daly et al., 1999; Tam and Lu, 1998). Numerous studies have detailed the successful incorporation of linear bioactive peptides grafted onto the cyclotide framework, resulting in improved stability while maintaining potency and selectivity for their targets (Poth et al., 2013). "
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    ABSTRACT: Cyclotides combine the stability of disulfide-rich peptides with the intracellular accessibility of cell-penetrating peptides, giving them outstanding potential as drug scaffolds with an ability to inhibit intracellular protein-protein interactions. To realize and optimize the application of cyclotides as a drug framework and delivery system, we studied the ability of the prototypic cyclotide, kalata B1, to enter mammalian cells. We show that kalata B1 can enter cells via both endocytosis and direct membrane translocation. Both pathways are initiated by targeting phosphatidylethanolamine phospholipids at the cell surface and inducing membrane curvature. This unusual approach to initiate internalization might be harnessed to deliver drugs into cells and, in particular, cancer cells, which present a higher proportion of surface-exposed phosphatidylethanolamine phospholipids. Our findings highlight the potential of these peptides as drug leads for the modulation of traditionally "undruggable" targets, such as intracellular protein-protein interactions. Copyright © 2015 Elsevier Ltd. All rights reserved.
    No preview · Article · Aug 2015 · Chemistry & biology
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    • "where five α-helices enclose a dense hydrophobic core (González et al., 2000). Finally, one of the most emblematic families of circular AMP is that of cyclotides (Jagadish and Camarero, 2010): these are plant-derived peptides, with approximately 30 AA, characterized by a head-to-tail cyclic backbone and three or four disulfide bonds forming the so-called cyclic cysteine knot (CCK; Craik et al., 1999), for which they are also known as " knotted peptides. " As a result of their singular structure, these peptides are extremely stable, retaining their biological activity after boiling and being extremely resistant to enzymatic degradation (Vila-Perelló and Andreu, 2005; Craik and Conibear, 2011). "
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    ABSTRACT: A range of antimicrobial peptides (AMP) exhibit activity on malaria parasites, Plasmodium spp., in their blood or mosquito stages, or both. These peptides include a diverse array of both natural and synthetic molecules varying greatly in size, charge, hydrophobicity, and secondary structure features. Along with an overview of relevant literature reports regarding AMP that display antiplasmodial activity, this review makes a few considerations about those molecules as a potential new class of antimalarial drugs.
    Full-text · Article · Dec 2014 · Frontiers in Pharmacology
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    • "Cyclotides are stable in various physical and chemical conditions as a result of the CCK motif56. This is an attractive property of these peptides that can be used as a scaffold for designing therapeutic peptides, especially for improving the stability of linear peptides7891011. In addition, these peptides display cytotoxicity to microbes12, along with HIV-infected131415, cancer16 and tumor17 cells. "
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    ABSTRACT: Kalata B1 has been demonstrated to have bioactivity relating to membrane disruption. In this study, we conducted coarse-grained molecular dynamics simulations to gain further insight into kB1 bioactivity. The simulations were performed at various concentrations of kB1 to capture the overall progression of its activity. Two configurations of kB1 oligomers, termed tower-like and wall-like clusters, were detected. The conjugation between the wall-like oligomers resulted in the formation of a ring-like hollow in the kB1 cluster on the membrane surface. Our results indicated that the molecules of kB1 were trapped at the membrane-water interface. The interfacial membrane binding of kB1 induced a positive membrane curvature, and the lipids were eventually extracted from the membrane through the kB1 ring-like hollow into the space inside the kB1 cluster. These findings provide an alternative view of the mechanism of kB1 bioactivity that corresponds with the concept of an interfacial bioactivity model.
    Full-text · Article · Feb 2014 · Scientific Reports
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