| 1. |
- Strand, Malin, et al.
(författare)
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The Bacterial (Vibrio alginolyticus) Production of Tetrodotoxin in the Ribbon Worm Lineus longissimus-Just a False Positive?
- 2016
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Ingår i: Marine Drugs. - Basel : MDPI AG. - 1660-3397. ; 14:4
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Tidskriftsartikel (refereegranskat)abstract
- We test previous claims that the bacteria Vibrio alginolyticus produces tetrodotoxin (TTX) when living in symbiosis with the nemertean Lineus longissimus by a setup with bacteria cultivation for TTX production. Toxicity experiments on the shore crab, Carcinus maenas, demonstrated the presence of a paralytic toxin, but evidence from LC-MS and electrophysiological measurements of voltage-gated sodium channel-dependent nerve conductance in maleWistar rat tissue showed conclusively that this effect did not originate from TTX. However, a compound of similar molecular weight was found, albeit apparently non-toxic, and with different LC retention time and MS/MS fragmentation pattern than those of TTX. We conclude that C. maenas paralysis and death likely emanate from a compound <5 kDa, and via a different mechanism of action than that of TTX. The similarity in mass between TTX and the Vibrio-produced low-molecular-weight, non-toxic compound invokes that thorough analysis is required when assessing TTX production. Based on our findings, we suggest that re-examination of some published claims of TTX production may be warranted.
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| 2. |
- El-Seedi, Hesham R., et al.
(författare)
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Recent insights into the biosynthesis and biological activities of natural xanthones
- 2010
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Ingår i: Current Medicinal Chemistry. - : Bentham Science Publishers Ltd.. - 0929-8673 .- 1875-533X. ; 17:9, s. 854-901
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Forskningsöversikt (refereegranskat)abstract
- This review focuses on recent advances in our understanding of the complex biosynthetic pathways and diverse biological activities of naturally occurring xanthones. The biosynthesis section covers studies published from 1989 to 2008 on xanthone production in plants and fungi, while the bioactivity review presents tabulated activities of more than 250 xanthones described in studies published from 2001 to 2008, together with structural information and indications of their wide-ranging potential uses as pharmacological tools. A large number of relevant papers have been published on these subjects (128 cited here), illustrating the diversity of the xanthones and their possible uses.
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| 3. |
- Sjögren, M., et al.
(författare)
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Antifouling activity of brominated cyclopeptides from the marine sponge Geodia barretti
- 2004
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Ingår i: Journal of Natural Products. - : American Chemical Society (ACS). - 0163-3864 .- 1520-6025. ; 67:3, s. 368-372
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Tidskriftsartikel (refereegranskat)abstract
- In this work, we show the potent antifouling effects of two compounds, barettin (cyclo[(6-bromo-8-entryptophan)arginine]) (1), isolated as a Z/E mixture (87/13), and 8,9-dihydrobarettin (cyclo[(6-bromotryptophan)arginine]) (2), isolated from the marine sponge Geodia barretti. The compounds were isolated guided by their ability to inhibit the settlement of cyprid larvae of the barnacle Balanus improvisus, and their structures were determined by means of mass spectrometry, NMR, and quantitative amino acid analysis. The activities of these brominated diketopiperazine-like cyclic dipeptides are in the range of antifouling agents in use today, as shown by their EC50 values of 0.9 and 7.9 muM, respectively. However, contrary to today's antifouling agents, the effects of barettin and 8,9-dihydrobarettin are nontoxic and reversible. A small set of synthetic analogues, including L-arginine, L-tryptophan, 5-bromo-D,L-tryptophan, 6-bromo-D,L-tryptophan, and 6-fluoro-D,L-tryptophan, were tested for possible structure-activity relationships. None of these compounds showed any effect at a concentration of 10 muM. We hypothesize that the isolated compounds are part of the sponge's chemical defense to deter fouling organisms. This theory is supported by the fact that barettin is found in water exposed to living specimens of G. barretti in concentrations that completely inhibit barnacles from settling.
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| 4. |
- Wang, Conan, et al.
(författare)
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Combined X-ray and NMR analysis of the stability of the cyclotide cystine knot fold that underpins its insecticidal activity and potential use as a drug scaffold
- 2009
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Ingår i: Journal of Biological Chemistry. - 0021-9258 .- 1083-351X. ; 284:16, s. 10672-10683
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Tidskriftsartikel (refereegranskat)abstract
- Cyclotides are a family of plant defense proteins that are highly resistant to adverse chemical, thermal, and enzymatic treatment. Here, we present the first crystal structure of a cyclotide, varv F, from the European field pansy, Viola arvensis, determined at a resolution of 1.8 angstrom. The solution state NMR structure was also determined and, combined with measurements of biophysical parameters for several cyclotides, provided an insight into the structural features that account for the remarkable stability of the cyclotide family. The x-ray data confirm the cystine knot topology and the circular backbone, and delineate a conserved network of hydrogen bonds that contribute to the stability of the cyclotide fold. The structural role of a highly conserved Glu residue that has been shown to regulate cyclotide function was also determined, verifying its involvement in a stabilizing hydrogen bond network. We also demonstrate that varv F binds to dodecylphosphocholine micelles, defining the binding orientation and showing that its structure remains unchanged upon binding, further demonstrating that the cyclotide fold is rigid. This study provides a biological insight into the mechanism by which cyclotides maintain their native activity in the unfavorable environment of predator insect guts. It also provides a structural basis for explaining how a cluster of residues important for bioactivity may be involved in self-association interactions in membranes. As well as being important for their bioactivity, the structural rigidity of cyclotides makes them very suitable as a stable template for peptide-based drug design.
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| 5. |
- Kerr White, John, et al.
(författare)
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A Synthetic Cyclized Antimicrobial Peptide with Potent Effects against Drug-Resistant Skin Pathogens
- 2023
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Ingår i: ACS - Infectious Diseases. - : American Chemical Society (ACS). - 2373-8227. ; 9:5, s. 1056-1063
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Tidskriftsartikel (refereegranskat)abstract
- Dermal infections requiring treatment are usually treated with conventional antibiotics, but the rise of bacterial resistance to first-line antibiotics warrants alternative therapeutics. Here, we report that a backbone-cyclized antimicrobial peptide, CD4-PP, designed from the human host defense peptide LL-37, has strong direct antibacterial effects on antibiotic sensitive as well as resistant-type strains and clinical isolates of common skin pathogens in the low (<2) μM range. In addition, it influences innate immunity in keratinocytes, and treatment with CD4-PP is able to clear bacterial infections in infected keratinocytes. Additionally, CD4-PP treatment significantly reduces the wound area in a lawn of keratinocytes infected with MRSA. In conclusion, CD4-PP has the potential to serve as a future drug treating wounds infected with antibiotic-resistant bacteria.
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| 6. |
- Aboye, Teshome L., et al.
(författare)
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A Cactus-Derived Toxin-Like Cystine Knot Peptide with Selective Antimicrobial Activity
- 2015
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Ingår i: ChemBioChem. - : Wiley. - 1439-4227 .- 1439-7633. ; 16:7, s. 1068-1077
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Tidskriftsartikel (refereegranskat)abstract
- Naturally occurring cystine knot peptides show a wide range of biological activity, and as they have inherent stability they represent potential scaffolds for peptide-based drug design and biomolecular engineering. Here we report the discovery, sequencing, chemical synthesis, three-dimensional solution structure determination and bioactivity of the first cystine knot peptide from Cactaceae (cactus) family: Ep-AMP1 from Echinopsis pachanoi. The structure of Ep-AMP1 (35 amino acids) conforms to that of the inhibitor cystine knot (or knottin) family but represents a novel diverse sequence; its activity was more than 500 times higher against bacterial than against eukaryotic cells. Rapid bactericidal action and liposome leakage implicate membrane permeabilisation as the mechanism of action. Sequence homology places Ec-AMP1 in the plant C6-type of antimicrobial peptides, but the three dimensional structure is highly similar to that of a spider neurotoxin.
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| 7. |
- Pränting, Maria, et al.
(författare)
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The cyclotide cycloviolacin O2 from Viola odorata has potent bactericidal activity against Gram-negative bacteria
- 2010
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Ingår i: Journal of Antimicrobial Chemotherapy. - : Oxford University Press (OUP). - 0305-7453 .- 1460-2091. ; 65:9, s. 1964-1971
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Tidskriftsartikel (refereegranskat)abstract
- 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.CONCLUSIONS: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.
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| 8. |
- Sjögren, Martin, et al.
(författare)
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Two Brominated Cyclic Dipeptides Released by the Coldwater Marine Sponge Geodia barretti Act in Synergy As Chemical Defense
- 2011
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Ingår i: Journal of natural products (Print). - : American Chemical Society (ACS). - 0163-3864 .- 1520-6025. ; 74:3, s. 449-454
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Tidskriftsartikel (refereegranskat)abstract
- The current work shows that two structurally similar cyclodipeptides, barettin (1) and 8,9-dihydrobarettin (2), produced by the coldwater marine sponge Geodia barretti Bowerbank act in synergy to deter larvae of surface settlers and may also be involved in defense against grazers. Previously, 1 and 2 were demonstrated to bind specifically to serotonergic 5-HT receptors. It may be suggested that chemical defense in G. barretti involves a synergistic action where one of the molecular targets is a 5-HT receptor. A mixture of 1 and 2 lowered the EC50 of larval settlement as compared to the calculated theoretical additive effect of the two compounds. Moreover, an in situ sampling at 120 m depth using a remotely operated vehicle revealed that the sponge releases these two compounds to the ambient water. Thus, it is suggested that the synergistic action of 1 and 2 may benefit the sponge by reducing the expenditure of continuous production and release of its chemical defense substances. Furthermore, a synergistic action between structurally closely related compounds produced by the same bioenzymatic machinery ought to be the most energy effective for the organism and, thus, is more common than synergy between structurally indistinct compounds.
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| 9. |
- Hedner, E., et al.
(författare)
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Brominated cyclodipeptides from the marine sponge Geodia barretti as selective 5-HT ligands
- 2006
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Ingår i: Journal of Natural Products. - : American Chemical Society (ACS). - 0163-3864 .- 1520-6025. ; 69:10, s. 1421-1424
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Tidskriftsartikel (refereegranskat)abstract
- The brominated cyclodipeptides barettin(cyclo[(6-bromo-8-entryptophan) arginine]) and 8,9-dihydrobarettin ( cyclo[(6-bromotryptophan) arginine]) isolated from the marine sponge Geodia barretti have previously been shown to inhibit settlement of barnacle larvae in a dose-dependent manner in concentrations ranging from 0.5 to 25 mu M. To further establish the molecular target and mode of action of these compounds, we investigated their affinity to human serotonin receptors. The tryptophan residue in the barettins resembles that of endogenous serotonin [5-hydroxytryptamine]. A selection of human serotonin receptors, including representatives from all subfamilies (1-7), were transfected into HEK-293 cells. Barettin selectively interacted with the serotonin receptors 5-HT2A, 5-HT2C, and 5-HT4 at concentrations close to that of endogenous serotonin, with the corresponding K-i values being 1.93, 0.34, and 1.91 mu M, respectively. 8,9-Dihydrobarettin interacted exclusively with the 5-HT2C receptor with a K-i value of 4.63 mu M; it failed to show affinity to 5-HT2A and 5-HT4, indicating that the double bond between the tryptophan and arginine residue plays an important role in the interaction with the receptor proteins.
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| 10. |
- Rajendran, Sanjeevan, et al.
(författare)
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Screening for Cyclotides in Sri Lankan Medicinal Plants : Discovery, Characterization, and Bioactivity Screening of Cyclotides from Geophila repens
- 2023
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Ingår i: Journal of Natural Products. - : American Chemical Society (ACS). - 0163-3864 .- 1520-6025. ; 86:1, s. 52-65
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Tidskriftsartikel (refereegranskat)abstract
- Cyclotides are an intriguing class of structurally stable circular miniproteins of plant origin with numerous potential pharmaceutical and agricultural applications. To investigate the occurrence of cyclotides in Sri Lankan flora, 50 medicinal plants were screened, leading to the identification of a suite of new cyclotides from Geophila repens of the family Rubiaceae. Cycloviolacin O2-like (cyO2-like) gere 1 and the known cyclotide kalata B7 (kB7) were among the cyclotides characterized at the peptide and/or transcript level together with several putative enzymes, likely involved in cyclotide biosynthesis. Five of the most abundant cyclotides were isolated, sequenced, structurally characterized, and screened in antimicrobial and cytotoxicity assays. All gere cyclotides showed cytotoxicity (IC50 of 2.0-10.2 mu M), but only gere 1 inhibited standard microbial strains at a minimum inhibitory concentration of 4-16 mu M. As shown by immunohistochemistry, large quantities of the cyclotides were localized in the epidermis of the leaves and petioles of G. repens. Taken together with the cytotoxicity and membrane permeabilizing activities, this implicates gere cyclotides as potential plant defense molecules. The presence of cyO2-like gere 1 in a plant in the Rubiaceae supports the notion that phylogenetically distant plants may have coevolved to express similar cytotoxic cyclotides for a specific functional role, most likely involving host defense.
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