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Cyclotides from an Extreme Habitat: Characterization of Cyclic Peptides from Viola abyssinica of the Ethiopian Highlands
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy. (Göransson)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy. (Göransson)
Addis Ababa University.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy. (Göransson)
2011 (English)In: Journal of natural products (Print), ISSN 0163-3864, E-ISSN 1520-6025, Vol. 74, no 4, 727-731 p.Article in journal (Refereed) Published
Abstract [en]

As part of ongoing explorations of the structural diversity of cyclotides, the cyclotide content of a native violet of the East African highlands, Viola abyssinica (which grows at altitudes up to 3400 m), was studied. Six new cyclotides, vaby A-E (1-5) and varv E (6), were isolated and characterized by employing HPLC and MS techniques and quantitative amino acid analysis. Cyclotides 1-5 were found to have new sequences, and 1-3 have a further novel feature in their sequences, an alanine moiety in loop 2. Two of the cyclotides (1 and 4) also exhibited cytotoxic properties in a flourometric microculture cytotoxicity assay. The findings corroborate the hypothesis that investigating the cyclotide contents of violets growing in diverse environments is a promising approach for extending our knowledge of both the structural and biological diversity of cyclotides.

Place, publisher, year, edition, pages
American chemical society , 2011. Vol. 74, no 4, 727-731 p.
Keyword [en]
cyclotide, Viola abyssinica
National Category
Medical and Health Sciences
Research subject
Pharmacognosy
Identifiers
URN: urn:nbn:se:uu:diva-161105DOI: 10.1021/np100790fISI: 000289742300029OAI: oai:DiVA.org:uu-161105DiVA: diva2:454454
Available from: 2011-11-07 Created: 2011-11-07 Last updated: 2017-12-08Bibliographically approved
In thesis
1. Cyclotides: Tuning Parameters Toward Their Use in Drug Design
Open this publication in new window or tab >>Cyclotides: Tuning Parameters Toward Their Use in Drug Design
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Cyclotides are plant proteins with a unique topology, defined as the cyclic cystine knot motif. The motif endows cyclotides with exceptional chemical and biological stability. They also exhibit a wide range of biological activities including insecticidal, cytotoxic, anti-HIV and antimicrobial effects. Hence, cyclotides have become potential candidates in the development of peptide-based drugs; either as scaffolds to stabilize susceptible peptide sequences or as drugs by their own right. In this thesis, important parameters that could be inputs toward this development have been tuned.

An extraction protocol that can be extended to industrial scale production of the cyclotides from natural sources was developed; accordingly, a single maceration with hydroalcoholic solutions of medium polarity represented an optimum extraction method.

Moreover, it was shown that investigating the cyclotide content of cyclotide-bearing plants from diverse environments is a promising approach for extending the knowledge of both structural and biological diversity of these proteins. Five novel cyclotides with new sequence diversity were isolated and characterized from a violet that grows on Ethiopian highlands at an altitude of 3400 m.

One of the areas where the cyclotide framework has attracted interest is the development of stable antimicrobial peptides. A stability study was carried out to determine the stability of the cyclotide framework in a cocktail of bacterial proteases and serum where the native forms of tested cyclotides exhibited high stability profile.

Understanding the modes of cyclotide-cell interaction is certainly an important factor for the potential development of cyclotide-based drugs. Cellular studies were carried out using the comet assay and microautoradiography. A bell-shaped dose response curve was obtained for the DNA damaging effect of the cyclotides in the comet assay, which was the first toxicological assay of its kind on this class of proteins. The microautoradiography study revealed that the cyclotides penetrate into the cells even at cytotoxic concentrations. From previous reports, it was known that the cyclotides interact with membranes; the cellular studies in this thesis added to this knowledge by clearly demonstrating that these proteins have multiple modes of action. 

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2012. 81 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 156
Keyword
cyclotide, Viola abyssinica, Viola odorata, Extraction, Violaceae, vaby, cytotoxic, genotoxic, cell penetrating, microautoradiography, LC-MS, comet assay, cycloviolacin O2
National Category
Medical and Health Sciences Natural Sciences
Research subject
Pharmacognosy
Identifiers
urn:nbn:se:uu:diva-169712 (URN)978-91-554-8307-4 (ISBN)
Public defence
2012-04-26, B41, Husargatan 3, Biomedical Center, Uppsala University, Uppsala, 10:15 (English)
Opponent
Supervisors
Available from: 2012-04-04 Created: 2012-03-05 Last updated: 2012-04-19Bibliographically approved

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