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Distribution and Ch...
Distribution and Chemical Diversity of Cyclotides from Violaceae : Impact of Structure on Cytotoxic Activity and Membrane Interactions
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- Burman, Robert, 1979- (författare)
- Uppsala universitet,Avdelningen för farmakognosi
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- Göransson, Ulf, Assistant Professor (preses)
- Uppsala universitet,Avdelningen för farmakognosi
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- Bohlin, Lars, Professor (preses)
- Uppsala universitet,Avdelningen för farmakognosi
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- Gerwick, William, Professor (opponent)
- University of California, San Diego
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(creator_code:org_t)
- ISBN 9789155479039
- Uppsala : Acta Universitatis Upsaliensis, 2010
- Engelska 70 s.
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Serie: Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, 1651-6192 ; 130
- Relaterad länk:
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https://uu.diva-port... (primary) (Raw object)
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https://urn.kb.se/re...
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Abstract
Ämnesord
Stäng
- During the last decade there has been increased interest in the cyclotide protein family, which consist of a circular chain of approximately 30 amino acids, including six cysteines that form three disulfide bonds, arranged in a cyclic cystine knot motif. This thesis gives new insights in cyclotide distribution and occurrence in the plant family Violaceae, structure-activity relationships for cytotoxic effects, membrane disruption and adsorption on lipid membranes, and evaluates toxicity and anti-tumor activity in vivo. A large-scale analysis was done on over 200 samples covering 17 of the 23 genera in Violaceae, and cyclotides were positively identified in almost 150 of approximately 900 known species. Conclusions are that the Violaceae is an extremely rich source of cyclotides, and that they are ubiquitous among all species in that plant family. After investigating the cyclotides' cytotoxicity it was evident that the effects were immediate and occurred at low micromolar concentrations. To understand the relationships between structure and activity, approximately 30 cyclotides and cyclotide derivates were assayed for cytotoxicity. Results showed that the overall charge is of minor influence on activity and revealed a strong correlation between an intact hydrophobic molecular surface and cytotoxic effect. The cytotoxic activity is mainly due to interactions between peptides and target membranes, illustrated by prototypic cyclotides' ability to induce liposome leakage and adsorb to lipid membranes. Cyclotides were strongly lytic against zwitterionic liposomes, less when cholesterol was included, while for anionic liposomes, activity depend on the net charge of cyclotide. A similar pattern was observed for the adsorption of the cyclotides to anionic bilayers, in which strong lytic activity was coupled with high adsorption. To further evaluate cyclotides cytotoxic effects, in vivo studies were conducted, both for acute toxicity and anti-tumor efficacy in mice. Two different methods were used: hollow fiber method and traditional xenografts, but no significant anti-tumor effects were detected. The results indicate that anti-tumor effects are minor or absent at tolerable doses and that cyclotides have a very abrupt in vivo toxicity profile, with lethality after single injection at 2.0 mg/kg.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Farmaceutiska vetenskaper (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Pharmaceutical Sciences (hsv//eng)
Nyckelord
- Cyclotide
- Violaceae
- Viola
- Cytotoxic
- Mechanism
- In vivo
- Structure-activity
- Membrane
- Mass spectrometry
- Pharmacognosy
- Farmakognosi
- Pharmacognosy
- Farmakognosi
Publikations- och innehållstyp
- vet (ämneskategori)
- dok (ämneskategori)
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