Article

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: 2.29). 01/2010; 94(5):611-6. DOI: 10.1002/bip.21433
Source: PubMed

ABSTRACT Cyclotides are a new emerging family of large plant-derived backbone-cyclized polypeptides (approximately 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.

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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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    • "They contain a unique structural motif that consists of a head-to-tail cyclic backbone and knotted arrangement of three disulfide bonds, together referred to as the cyclic cystine knot (CCK) [4]. This motif engenders cyclotides with exceptional resistance to thermal, chemical and enzymatic degradation [2], and they are therefore an attractive scaffold for the design of peptide-based therapeutics [1] [9] [15]. "
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    ABSTRACT: Cyclotides are a large family of plant peptides characterized by a macrocyclic backbone and knotted arrangement of three disulfide bonds. This unique structure renders cyclotides exceptionally stable to thermal, chemical and enzymatic treatments. They exhibit a variety of bioactivities, including uterotonic, anti-HIV, cytotoxic and hemolytic activity and it is these properties that make cyclotides an interesting peptide scaffold for drug design. In this study, eight new cyclotides (Viphi A-H), along with eight known cyclotides, were isolated from Viola philippica, a plant from the Violaceae family. In addition, Viba 17 and Mram 8 were isolated for the first time as peptides. The sequences of these cyclotides were elucidated primarily by using a strategy involving reduction, enzymatic digestion and tandem mass spectroscopy sequencing. Several of the cyclotides showed cytotoxic activities against the cancer cell lines MM96L, HeLa and BGC-823. The novel cyclotides reported here: (1) enhance the known sequence variation observed for cyclotides; (2) extend the number of species known to contain cyclotides; (3) provide interesting structure-activity relationships that delineate residues important for cytotoxic activity. In addition, this study provides insights into the potential active ingredients of traditional Chinese medicines.
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    • "They can also be encoded within standard cloning vectors and readily expressed in bacteria or animal cells [26] [70], thus making them ideal substrates for molecular evolution strategies to enable generation and selection of compounds with optimal binding and inhibitory characteristics using high throughput cellbased assays [106]. All of these characteristics make cyclotides appear as very promising leads or frameworks for development of peptide-based therapeutics and diagnostics [27] [68] [105] [107] Abbreviations "
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    ABSTRACT: Cyclotides are a growing family of large plant-derived backbone-cyclized polypeptides (≈30 amino acids long) that share a disulfide-stabilized core characterized by an unusual knotted structure. Their unique circular backbone topology and knotted arrangement of three disulfide bonds makes 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, biological activities and ability to cross the cell membrane, cyclotides can be exploited to develop new peptide-based drugs with high potential for success. The cyclotide scaffold can be engineered or evolved using molecular evolution to inhibit protein-protein interactions implicated in cancer and other human diseases, or design new antimicrobial. The present review reports the biological diversity and therapeutic potential of natural and engineered cyclotides.
    Current Molecular Pharmacology 11/2010; 3(3):153-63. DOI:10.2174/1874-470211003030153
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