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Cycloviolacin O2 peptide – Plant antimicrobial peptide as potential anticancer agents

Cyclotide

Cycloviolacin O2 peptide (CyO2) is a cyclotide isolated from Viola odorata. Cyclotides are circular peptides with remarkable characteristics including a head-to-tail cyclized backbone and 6 cysteine residues forming cyclic-cystine-knot motif (CCK) by three disulfide bonds. Cyclotides show potent cytotoxic activity that’s why they represent novel range of cytotoxic agents.

Cycloviolacin O2 peptide

Cycloviolacin O2 has antitumor effect and specific membrane-disrupting activity resulting in cell death and appears to be selective to tumoral cells. CyO2 has also demonstrated a potent bactericidal activity against Gram – bacteria with a MIC of 2.2µM on E. coli. Cycloviolacin O2 provides a potential scaffold for future drug design.
Cycloviolacin O2 peptide is a head-to-tail cyclic peptide with three disulfide bridges between 1-4, 2-5 and 3-6.

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CYCLOVIOLACIN

 

Technical specification

 Cycloviolacin O2 peptide Sequence : GIPCGESCVWIPCISSAIGCSCKSKVCYRN
Cycloviolacin O2 peptide MW : 3164,75 g/mol (C133H215N37O40S6)
Cycloviolacin O2 peptide Purity : > 95%
Cycloviolacin O2 peptide Counter-Ion : TFA Salts (see option TFA removal)
Peptide library synthesis Cycloviolacin O2 peptide Delivery format : Freeze dried in propylene 2mL microtubes
peptide solubility guidelines Peptide Solubility Guideline
buy peptide price Bulk peptide quantities available

 

Price

Product catalog Size Price € HT Price $ HT
SB111-0.1MG 0.1 mg 450 563
SB111-0.5MG 0.5 mg 1575 1970

 

References

1- Guzman-Rodriguez J. J. et al. Biomed Res Int. 2015:735087 (2015)
Plant antimicrobial peptides as potential anticancer agents

 

Antimicrobial peptides (AMPs) are part of the innate immune defense mechanism of many organisms and are promising candidates to treat infections caused by pathogenic bacteria to animals and humans. AMPs also display anticancer activities because of their ability to inactivate a wide range of cancer cells. Cancer remains a cause of high morbidity and mortality worldwide. Therefore, the development of methods for its control is desirable. Attractive alternatives include plant AMP thionins, defensins, and cyclotides, which have anticancer activities. Here, we provide an overview of plant AMPs anticancer activities, with an emphasis on their mode of action, their selectivity, and their efficacy.

2- Gerlach S. L. et al. Biopolymers. 94(5):617-625 (2010)
Anticancer and chemosensitizing abilities of cycloviolacin 02 from Viola odorata and psyle cyclotides from Psychotria leptothyrsa

 

Cycloviolacin O2 (CyO2), a cyclotide from Viola odorata (Violaceae) has antitumor effects and causes cell death by membrane permeabilization. In the breast cancer line, MCF-7 and its drug resistant subline MCF-7/ADR, the cytotoxic effects of CyO2 (0.2-10 microM) were monitored in the presence and absence of doxorubicin (0.1-5 microM) using cell proliferation assays to establish its chemosensitizing abilities. SYTOX Green assays were Sperformed to verify membrane permeabilization and showed cellular disruption correlates with cyclotide chemosensitization. Fluorescence microscopy studies demonstrated increased cellular internalization of doxorubicin in drug resistant cells when coexposed to CyO2. Interestingly, CyO2 did not produce significant membrane disruption in primary human brain endothelial cells, which suggested cyclotide specificity toward induced pore formation in highly proliferating tumor cells. Furthermore, three novel cyclotides (psyle A, C and E) from Psychotria leptothyrsa (Rubiaceae) were also monitored for cytotoxic activity. The cyclotides displayed potent cytotoxicity (IC50 = 0.64->10 microM), and coexposure to cyclotides significantly enhanced doxorubicin induced toxicity (IC50 = 0.39-0.76 microM). This study documents several cyclotides with robust cytotoxicity that may be promising chemosensitizing agents against drug resistant breast cancer.

3- Svangard E, Burman R, Gunasekera S, Lovborg H, Gullbo J and Goransson U. J Nat Prod. 70(4):643-647 (2007)
Mechanism of action of cytotoxic cyclotides: cycloviolacin O2 disrupts lipid membranes

 

In recent years, the cyclotides have emerged as the largest family of naturally cyclized proteins. Cyclotides display potent cytotoxic activity that varies with the structure of the proteins, and combined with their unique structure, they represent novel cytotoxic agents. However, their mechanism of action is yet unknown. In this work we show that disruption of cell membranes plays a crucial role in the cytotoxic effect of the cyclotide cycloviolacin O2 (1), which has been isolated from Viola odorata. Cell viability and morphology studies on the human lymphoma cell line U-937 GTB showed that cells exposed to 1 displayed disintegrated cell membranes within 5 min. Functional studies on calcein-loaded HeLa cells and on liposomes showed rapid concentration-dependent release of their respective internal contents. The present results show that cyclotides have specific membrane-disrupting activity.

4- Pranting M, Loov C, Burman R, Goransson U and Andersson D. I. J Antimicrob Chemother. 65(9):1964-71 (2010)
The cyclotide cycloviolacin O2 from Viola odorata has potent bactericidal activity against Gram-negative bacteria

 

OBJECTIVES: To determine the antibacterial activity of small cyclic plant proteins, i.e. cyclotides, and the importance of the surface exposed charged residues for activity.

METHODS: Prototypic cyclotides, including the Möbius kalata B1 and the bracelet cycloviolacin O2 (cyO2), were isolated using reversed-phase HPLC. Initial activity screenings were conducted using radial diffusion assays (RDAs) and MIC assays with Salmonella enterica serovar Typhimurium LT2, Escherichia coli and Staphylococcus aureus as test strains. For the most active peptide, cyO2, time-kill kinetics was determined in sodium phosphate buffer (containing 0.03% trypticase soy broth) against several Gram-negative and Gram-positive bacterial species. Charged residues in cyO2 were chemically modified and activity was determined in time-kill assays.

RESULTS: CyO2 was the most active cyclotide and efficiently inhibited the growth of S. enterica serovar Typhimurium LT2 and E. coli in RDAs and MIC assays, while the other peptides were less active. In time-kill assays, cyO2 also had bactericidal activity against the Gram-negative species Klebsiella pneumoniae and Pseudomonas aeruginosa. In contrast, none of the cyclotides had high activity against S. aureus. Chemical masking of the charged Glu and Lys residues in cyO2 caused a near total loss of activity against Salmonella, while masking Arg caused a less pronounced activity reduction.

CONCLUSION: CyO2 is a cyclotide with potent activity against Gram-negative bacteria. The charged residues in cyO2 are all required for optimum antibacterial activity. In combination with its previously demonstrated cytotoxic activity against cancer cells and the general stability of cyclotides, cyO2 provides a promising scaffold for future drug design.

5- Colgrave ML, Kotze AC, Ireland DC, Wang CK and Craik DJ. Chembiochem. 9(12):1939-45 (2008)
The anthelmintic activity of the cyclotides: natural variants with enhanced activity

 

The cyclotides are a family of backbone-cyclised cystine-knot-containing peptides from plants that possess anthelmintic activity against Haemonchus contortus and Trichostrongylus colubriformis, two important gastrointestinal nematode parasites of sheep. In the current study, we investigated the in vitro effects of newly discovered natural cyclotides on the viability of larval and adult life stages of these pests. The natural variants cycloviolacin O2, cycloviolacin O3, cycloviolacin O8, cycloviolacin O13, cycloviolacin O14, cycloviolacin O15, and cycloviolacin O16 extracted from Viola odorata showed up to 18-fold greater potency than the prototypic cyclotide kalata B1 in nematode larval development assays. Cycloviolacin O2 and cycloviolacin O14 were significantly more potent than kalata B1 in adult H. contortus motility assays. The lysine and glutamic acid residues of cycloviolacin O2, the most potent anthelmintic cyclotide, were chemically modified to investigate the role of these charged residues in modulating the biological activity. The single glutamic acid residue, which is conserved across all known cyclotides, was shown to be essential for activity, with a sixfold decrease in potency of cycloviolacin O2 following methylation. The three lysine residues present in cycloviolacin O2 were acetylated to effectively mask the positive charge, resulting in a 18-fold decrease in anthelmintic activity. The relative anthelmintic activities of the natural variants assayed against nematode larvae correlated with the number of charged residues present in their sequence.