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  • 1.
    Aboye, Teshome L.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Strömstedt, Adam A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Gunasekera, Sunithi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Bruhn, Jan G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    El-Seedi, Hesham
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Rosengren, K. Johan
    Göransson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    A Cactus-Derived Toxin-Like Cystine Knot Peptide with Selective Antimicrobial Activity2015In: ChemBioChem (Print), ISSN 1439-4227, E-ISSN 1439-7633, Vol. 16, no 7, p. 1068-1077Article in journal (Refereed)
    Abstract [en]

    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.

  • 2.
    Aboye, Teshome Leta
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Clark, Richard J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Burman, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Roig, Marta Bajona
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Craik, David J.
    University of Queensland, Institute for Molecular Bioscience.
    Göransson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Interlocking disulfides in circular proteins: toward efficient oxidative folding of cyclotides.2011In: Antioxidants and Redox Signaling, ISSN 1523-0864, E-ISSN 1557-7716, Vol. 14, no 1, p. 77-86Article in journal (Refereed)
    Abstract [en]

    Cyclotides are ultrastable plant proteins characterized by the presence of a cyclic amide backbone and three disulfide bonds that form a cystine knot. Because of their extreme stability, there has been significant interest in developing these molecules as a drug design scaffold. For this potential to be realized, efficient methods for the synthesis and oxidative folding of cyclotides need to be developed, yet we currently have only a basic understanding of the folding mechanism and the factors influencing this process. In this study, we determine the major factors influencing oxidative folding of the different subfamilies of cyclotides. The folding of all the cyclotides examined was heavily influenced by the concentration of redox reagents, with the folding rate and final yield of the native isomer greatly enhanced by high concentrations of oxidized glutathione. Addition of hydrophobic solvents to the buffer also enhanced the folding rates and appeared to alter the folding pathway. Significant deamidation and isoaspartate formation were seen when oxidation conditions were conducive to slow folding. The identification of factors that influence the folding and degradation pathways of cyclotides will facilitate the development of folding screens and optimized conditions for producing cyclotides and grafted analogs as stable peptide-based therapeutics.

  • 3. Arnison, Paul G.
    et al.
    Bibb, Mervyn J.
    Bierbaum, Gabriele
    Bowers, Albert A.
    Bugni, Tim S.
    Bulaj, Grzegorz
    Camarero, Julio A.
    Campopiano, Dominic J.
    Challis, Gregory L.
    Clardy, Jon
    Cotter, Paul D.
    Craik, David J.
    Dawson, Michael
    Dittmann, Elke
    Donadio, Stefano
    Dorrestein, Pieter C.
    Entian, Karl-Dieter
    Fischbach, Michael A.
    Garavelli, John S.
    Göransson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Gruber, Christian W.
    Haft, Daniel H.
    Hemscheidt, Thomas K.
    Hertweck, Christian
    Hill, Colin
    Horswill, Alexander R.
    Jaspars, Marcel
    Kelly, Wendy L.
    Klinman, Judith P.
    Kuipers, Oscar P.
    Link, A. James
    Liu, Wen
    Marahiel, Mohamed A.
    Mitchell, Douglas A.
    Moll, Gert N.
    Moore, Bradley S.
    Mueller, Rolf
    Nair, Satish K.
    Nes, Ingolf F.
    Norris, Gillian E.
    Olivera, Baldomero M.
    Onaka, Hiroyasu
    Patchett, Mark L.
    Piel, Joern
    Reaney, Martin J. T.
    Rebuffat, Sylvie
    Ross, R. Paul
    Sahl, Hans-Georg
    Schmidt, Eric W.
    Selsted, Michael E.
    Severinov, Konstantin
    Shen, Ben
    Sivonen, Kaarina
    Smith, Leif
    Stein, Torsten
    Suessmuth, Roderich D.
    Tagg, John R.
    Tang, Gong-Li
    Truman, Andrew W.
    Vederas, John C.
    Walsh, Christopher T.
    Walton, Jonathan D.
    Wenzel, Silke C.
    Willey, Joanne M.
    van der Donk, Wilfred A.
    Ribosomally synthesized and post-translationally modified peptide natural products: overview and recommendations for a universal nomenclature2013In: Natural product reports (Print), ISSN 0265-0568, E-ISSN 1460-4752, Vol. 30, no 1, p. 108-160Article, review/survey (Refereed)
    Abstract [en]

    This review presents recommended nomenclature for the biosynthesis of ribosomally synthesized and post-translationally modified peptides (RiPPs), a rapidly growing class of natural products. The current knowledge regarding the biosynthesis of the >20 distinct compound classes is also reviewed, and commonalities are discussed.

  • 4.
    Bohlin, Lars
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Alsmark, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Göransson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Klum, M.
    Weden, Christina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Backlund, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Strategies and methods for a sustainable search for bioactive compounds2012In: Planta Medica, ISSN 0032-0943, E-ISSN 1439-0221, Vol. 78, no 11, p. 1031-1032Article in journal (Other academic)
  • 5.
    Bohlin, Lars
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Göransson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Alsmark, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Wedén, Christina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Backlund, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Natural products in modern life science2010In: Phytochemistry Reviews, ISSN 1568-7767, E-ISSN 1572-980X, Vol. 9, no 2, p. 279-301Article in journal (Refereed)
    Abstract [en]

    With a realistic threat against biodiversity in rain forests and in the sea, a sustainable use of natural products is becoming more and more important. Basic research directed against different organisms in Nature could reveal unexpected insights into fundamental biological mechanisms but also new pharmaceutical or biotechnological possibilities of more immediate use. Many different strategies have been used prospecting the biodiversity of Earth in the search for novel structure-activity relationships, which has resulted in important discoveries in drug development. However, we believe that the development of multidisciplinary incentives will be necessary for a future successful exploration of Nature. With this aim, one way would be a modernization and renewal of a venerable proven interdisciplinary science, Pharmacognosy, which represents an integrated way of studying biological systems. This has been demonstrated based on an explanatory model where the different parts of the model are explained by our ongoing research. Anti-inflammatory natural products have been discovered based on ethnopharmacological observations, marine sponges in cold water have resulted in substances with ecological impact, combinatory strategy of ecology and chemistry has revealed new insights into the biodiversity of fungi, in depth studies of cyclic peptides (cyclotides) has created new possibilities for engineering of bioactive peptides, development of new strategies using phylogeny and chemography has resulted in new possibilities for navigating chemical and biological space, and using bioinformatic tools for understanding of lateral gene transfer could provide potential drug targets. A multidisciplinary subject like Pharmacognosy, one of several scientific disciplines bridging biology and chemistry with medicine, has a strategic position for studies of complex scientific questions based on observations in Nature. Furthermore, natural product research based on intriguing scientific questions in Nature can be of value to increase the attraction for young students in modern life science.

  • 6.
    Bohlin, Lars
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Göransson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Backlund, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Modern pharmacognosy: Connecting biology and chemistry2007In: Pure and Applied Chemistry, ISSN 0033-4545, E-ISSN 1365-3075, Vol. 79, no 4, p. 763-774Article in journal (Refereed)
    Abstract [en]

    In many countries today, the number of students selecting chemistry for higher studies is decreasing. At the same time, interest in the environmental aspects of chemistry, green chemistry, and sustainable use of natural products is increasing among the young generation of students. By modernizing and renewing a venerable proven science, pharmacognosy would have a strategic position to connect biology and chemistry. This multidisciplinary subject is important for discovery of novel and unique molecules with drug potential, and for revealing unknown targets, by studying evolutionary structure-activity optimization in nature. In this paper, the overall aim and strategies of our research are presented and exemplified by three different research projects.

    Natural products are involved in scientific issues important for a sustainable society, and a multidisciplinary subject such as pharmacognosy can, therefore, be useful in increasing future interest in both chemistry and biology.

  • 7.
    Boldbaatar, Delgerbat
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    El-Seedi, Hesham R.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Findakly, Meriana
    Jabri, Safa
    Javzan, Batkhuu
    Choidash, Battsetseg
    Göransson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Hellman, Bjorn
    Antigenotoxic and antioxidant effects of the Mongolian medicinal plant Leptopyrum fumarioides (L): An in vitro study2014In: Journal of Ethnopharmacology, ISSN 0378-8741, E-ISSN 1872-7573, Vol. 155, no 1, p. 599-606Article in journal (Refereed)
    Abstract [en]

    Ethnopharmacological relevance: Leptopyrum fumarioides has been used in the traditional medicine of Mongolia for the treatment of various diseases, including drug intoxications. However, since there is only sparse information about its chemistry, active components, and pharmacological and toxicological effects, the major aim of the present study employing mouse lymphoma cells was to evaluate the genotoxic and antigenotoxic/antioxidative effects of extracts and components isolated from this plant. Material and methods: A crude methanol extract was separated into three different sub-extracts: dichloromethane, n-butanol, and water. The major constituent of the n-butanol extract, i.e., the flavone luteolin-7-O-glucoside and a mixture of the most abundant compounds in the dichloromethane sub-extract were then isolated. DNA damage was evaluated using the comet assay; the antioxidant activity was evaluated using the DPPH radical scavenging assay. Results: The crude methanol extract, the dichloromethane sub-extract and the mixture of compounds isolated from the latter fraction, increased the level of DNA damage after three hours of exposure. In contrast, no increase in DNA damage was observed in the cells that had been exposed to the n-butanol and water sub-extracts, or to the pure flavone. When non-DNA damaging concentrations of extracts and compounds were tested together with the DNA damaging agent catechol, all sub-extracts were found to reduce the catechol-induced DNA damage (the flavone was then found to be the most effective protective agent). The n-butanol sub-extract and the flavone were also found to have the most prominent antioxidative effects. Conclusion: Based on the results from the present study, components in Leptopyrum fumarioides were found to protect the DNA damage induced by catechol, probably by acting as potent antioxidants.

  • 8.
    Boldbaatar, Delgerbat
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy. Natl Univ Mongolia, Sch Engn & Appl Sci, Ulaanbaatar 46, Mongol Peo Rep..
    Gunasekera, Sunithi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    El-Seedi, Hesham R.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy. Univ Malaya, Fac Sci, Dept Chem, Kuala Lumpur 50603, Malaysia..
    Göransson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Synthesis, Structural Characterization, and Bioactivity of the Stable Peptide RCB-1 from Ricinus communis2015In: Journal of natural products (Print), ISSN 0163-3864, E-ISSN 1520-6025, Vol. 78, no 11, p. 2545-2551Article in journal (Refereed)
    Abstract [en]

    The Ricinus communis biomarker peptides RCB-1 to -3 comprise homologous sequences of 19 (RCB-1) or 18 (RCB-2 and -3) amino acid residues. They all include four cysteine moieties, which form two disulfide bonds. However, neither the 3D structure nor the biological activity of any of these peptides is known. The synthesis of RCB-1, using microwave-assisted, Fmoc-based solid-phase peptide synthesis, and a method for its oxidative folding are reported. The tertiary structure of RCB-1, subsequently established using solution-state NMR, reveals a twisted loop fold with antiparallel ?-sheets reinforced by the two disulfide bonds. Moreover, RCB-1 was tested for antibacterial, antifungal, and cytotoxic activity, as well as in a serum stability assay, in which it proved to be remarkably stable.

  • 9. Broussalis, Adriana M.
    et al.
    Göransson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Coussio, Jorge D.
    Ferraro, Graciela
    Martino, Virginia
    Claeson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    First cyclotide from Hybanthus (Violaceae)2001In: Phytochemistry, ISSN 0031-9422, E-ISSN 1873-3700, Vol. 58, no 1, p. 47-51Article in journal (Refereed)
    Abstract [en]

    Hypa A, a novel macrocyclic polypeptide containing 30 amino acid residues, has been isolated from the n-butanol extract of the Argentine plant Hybanthus parviflorus. The sequence, cyclo-(SCVYIPCTITALLGCSCKNKVCYNGIPCAE), was determined by automated Edman degradation, quantitative amino acid analysis and nanospray MS/MS(2). Three intramolecular disulfide bridges stabilize the cyclic peptide backbone of hypa A. Using these structural features to classify the peptide as a cyclotide, we extended the distribution of that substance class to a new genus, and now propose a uniform nomenclature for cyclotides.

  • 10. Broussalis, Adriana M.
    et al.
    Göransson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Coussio, Jorge D.
    Ferraro, Graciela
    Martino, Virginia
    Claeson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    First cyclotide from Hybanthus (Violaceae)2001In: Phytochemistry, ISSN 0031-9422, E-ISSN 1873-3700, Vol. 58, no 1, p. 47-51Article in journal (Refereed)
    Abstract [en]

    Hypa A, a novel macrocyclic polypeptide containing 30 amino acid residues, has been isolated from the n-butanol extract of the Argentine plant Hybanthus parviflorus. The sequence, cyclo-(SCVYIPCTITALLGCSCKNKVCYNGIPCAE), was determined by automated Edman degradation, quantitative amino acid analysis and nanospray MS/MS2. Three intramolecular disulfide bridges stabilize the cyclic peptide backbone of hypa A. Using these structural features to classify the peptide as a cyclotide, we extended the distribution of that substance class to a new genus, and now propose a uniform nomenclature for cyclotides.

  • 11.
    Burman, Robert
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Gruber, Christian W
    Rizzardi, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Herrmann, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Craik, David J
    Gupta, Mahabir P
    Göransson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Cyclotide proteins and precursors from the genus Gloeospermum: filling a blank spot in the cyclotide map of Violaceae2010In: Phytochemistry, ISSN 0031-9422, E-ISSN 1873-3700, Vol. 71, no 1, p. 13-20Article in journal (Refereed)
    Abstract [en]

    Cyclotides are disulfide-rich plant proteins that are exceptional in their cyclic structure; their N and C termini are joined by a peptide bond, forming a continuous circular backbone, which is reinforced by three interlocked disulfide bonds. Cyclotides have been found mainly in the coffee (Rubiaceae) and violet (Violaceae) plant families. Within the Violaceae, cyclotides seem to be widely distributed, but the cyclotide complements of the vast majority of Violaceae species have not yet been explored. This study provides insight into cyclotide occurrence, diversity and biosynthesis in the Violaceae, by identifying mature cyclotide proteins, their precursors and enzymes putatively involved in their biosynthesis in the tribe Rinoreeae and the genus Gloeospermum. Twelve cyclotides from two Panamanian species, Gloeospermum pauciflorum Hekking and Gloeospermum blakeanum (Standl.) Hekking (designated Glopa A-E and Globa A-G, respectively) were characterised through cDNA screening and protein isolation. Screening of cDNA for the oxidative folding enzymes protein-disulfide isomerase (PDI) and thioredoxin (TRX) resulted in positive hits in both species. These enzymes have demonstrated roles in oxidative folding of cyclotides in Rubiaceae, and results presented here indicate that Violaceae plants have evolved similar mechanisms of cyclotide biosynthesis. We also describe PDI and TRX sequences from a third cyclotide-expressing Violaceae species, Viola biflora L., which further support this hypothesis.

  • 12.
    Burman, Robert
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Gunasekera, Sunithi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Strömstedt, Adam A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Göransson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Chemistry and Biology of Cyclotides: Circular Plant Peptides Outside the Box2014In: Journal of natural products (Print), ISSN 0163-3864, E-ISSN 1520-6025, Vol. 77, no 3, p. 724-736Article, review/survey (Refereed)
    Abstract [en]

    Cyclotides stand out as the largest family of circular proteins of plant origin hitherto known, with more than 280 sequences isolated at peptide level and many more predicted from gene sequences. Their unusual stability resulting from the signature cyclic cystine knot (CCK) motif has triggered a broad interest in these molecules for potential therapeutic and agricultural applications. Since the time of the first cyclotide discovery, our laboratory in Uppsala has been engaged in cyclotide discovery as well as the development of protocols to isolate and characterize these seamless peptides. We have also developed methods to chemically synthesize cyclotides by Fmoc-SPPS, which are useful in protein grafting applications. In this review, experience in cyclotide research over two decades and the recent literature related to their structures, synthesis, and folding as well the recent proof-of-concept findings on their use as "epitope" stabilizing scaffolds are summarized.

  • 13.
    Burman, Robert
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Herrmann, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Tran, Rosetti
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Kivelä, Jan-Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Lomize, Andrei
    University of Michigan, Little College of Pharmacy.
    Gullbo, Joachim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Göransson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Cytotoxic potency of small macrocyclic knot proteins: Structure-activity and mechanistic studies of native and chemically modified cyclotides2011In: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 9, no 11, p. 4306-4314Article in journal (Refereed)
    Abstract [en]

    The cyclotides are a family of circular and knotted proteins of natural origin with extreme enzymatic and thermal stability and active in a wide range of biological activities make them promising tools for pharmaceutical and crop-protection applications. The cyclotides are divided into two subfamilies depending on the presence (Möbius) or absence (bracelet) of a cis-Pro peptide bond. In the current work we report a series of experiments to give further insight into the structure activity relationship of cyclotides in general, and the differences between subfamilies and the role of their hydrophobic surface in particular. Selective chemical modifications of Glu, Arg, Lys and Trp residues was tested for cytotoxic activity and derivatives in which the Trp residue was modified showed low effect, suggesting the existence of a connection between hydrophobicity and activity. However, over the full set of cyclotides examined, there was no strong correlation between the cytotoxic activity and their hydrophobicity. Instead, it seems more like that the distribution of charged and hydrophobic residues determines the ultimate degree of potency. Furthermore, we found that while the Glu residue is very important in maintaining the activity of the bracelet cyclotide cycloviolacin O2, it is much less important in the Möbius cyclotides. However, despite these differences, a systematic test of mixtures of cyclotides, even from both subfamilies revealed that they act in an additive way.

     

  • 14.
    Burman, Robert
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Larsson, Sonny
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Yeshak, Mariamawit
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Rosengren, Johan
    University of Queensland, Institute for Molecular Bioscience.
    Craik, David
    University of Queensland, Institute for Molecular Bioscience.
    Göransson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Distribution of cicular peptides in plants: Large scale mapping of cyclotides in the ViolaceaeManuscript (preprint) (Other academic)
    Abstract [en]

    During last decade there has been increased interest in the small, cysteine-rich cyclotide proteins found in plant species of the violet family (Violaceae). These cyclotides 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. In this study we map the occurrence and distribution of cyclotides in the Violaceae. Plant material was obtained from herbarium sheets containing samples up to 200 years old. Even the oldest specimens exhibited a remarkable stability of cyclotides in the preserved leaves, with no degradation products observable, making them one of the most stable proteins in nature. We analyzed the cyclotide content in over 200 samples covering 17 of the 23 genera, and positively identified cyclotides in almost 150 of approximately 900 known species in the Violaceae. Each species contained a unique set of between one and 25 cyclotides, of which many were exclusive to individual species. The estimated number of different cyclotides in the Violaceae is 5,000-25,000. We conclude that the Violaceae is an extremely rich source of cyclotides, and we propose that cyclotides are ubiquitous among all Violaceae species.

  • 15.
    Burman, Robert
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Strömstedt, Adam A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Malmsten, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Göransson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Cyclotide-membrane interactions: defining factors of membrane binding, depletion and disruption2011In: Biochimica et Biophysica Acta - Biomembranes, ISSN 0005-2736, E-ISSN 1879-2642, Vol. 1808, no 11, p. 2665-2673Article in journal (Refereed)
    Abstract [en]

    The cyclotide family of plant-derived peptides is defined by a cyclic backbone and three disulfide bonds locked into a cyclic cystine knot. They display a diverse range of biological activities, many of which have been linked to an ability to target biological membranes. In the current work, we show that membrane binding and disrupting properties of prototypic cyclotides are dependent on lipid composition, using neutral (zwitterionic) membranes with or without cholesterol and/or anionic lipids. Cycloviolacin O2 (cyO2) caused potent membrane disruption, and showed selectivity towards anionic membranes, whereas kalata B1 and kalata B2 cyclotides were significantly less lytic towards all tested model membranes. To investigate the role of the charged amino acids of cyO2 in the membrane selectivity, these were neutralized using chemical modifications. In contrast to previous studies on the cytotoxic and antimicrobial effects of these derivatives, the Glu6 methyl ester of cyO2 was more potent than the native peptide. However, using membranes of Escherichia coil lipids gave the opposite result: the activity of the native peptide increased 50-fold. By using a combination of ellipsometry and LC-MS, we demonstrated that this unusual membrane specificity is due to native cyO2 extracting preferentially phosphatidylethanolamine-lipids from the membrane, i.e., PE-C16:0/cyC17:0 and PE-C16:0/C18:1.

  • 16.
    Burman, Robert
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Strömstedt, Adam A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Malmsten, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Göransson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Membrane integrity as a target for cyclotide cytotoxic activityManuscript (preprint) (Other academic)
    Abstract [en]

    The cyclotides are a family of plant-derived proteins that occur in plants from the Violaceae (violet) and Rubiaceae (coffee) families and have a diverse range of biological activities, including cytotoxic, hemolytic, antimicrobial, and insecticidal activities; the latter suggests their natural function lies in plant defense. In the current study we have investigated the membrane-disrupting and adsorption ability of prototypic cyclotides and correlated these findings to their cytotoxic properties. We also included modifications of selected charged amino acids in cycloviolacin O2, previously shown to be of importance for its cytotoxic activity. The cyclotides’ cytotoxic activity, ability to adsorb and disrupt model lipid membranes of different charge densities was investigated, e.g. by fluorescence spectroscopy, ellipsometry, and circular dichroism. Cytotoxicity of the native cyclotides was demonstrated to correlate to membrane adsorption and lytic activity. Hence, the activity of native cyclotides is mainly due to interactions between the proteins and the phospholipids in the target membrane. Striking effects of single amino acid variations in cycloviolacin O2 on its membrane interaction were also demonstrated.

     

  • 17.
    Burman, Robert
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Svedlund, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Felth, Jenny
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Hassan, Saadia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Herrmann, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Clark, Richard J.
    University of Queensland, Institute for Molecular Bioscience.
    Craik, David J.
    University of Queensland, Institute for Molecular Bioscience.
    Bohlin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Claeson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Göransson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Gullbo, Joachim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Evaluation of toxicity and anti-tumour activity of cycloviolacin O2 in mice.2010In: Biopolymers, ISSN 0006-3525, E-ISSN 1097-0282, Vol. 94, no 5, p. 626-634Article in journal (Refereed)
    Abstract [en]

    Cycloviolacin O2 is a small cyclic cysteine-rich protein belonging to the group of plant proteins called cyclotides. This cyclotide has been previously shown to exert cytotoxic activity against a variety of human tumor cell lines as well as primary cultures of human tumor cells in vitro. This study is the first evaluation of its tolerability and antitumor activity in vivo. Maximal-tolerated doses were estimated to 1.5 mg/kg for single intravenous (i.v.) dosing and 0.5 mg/kg for daily repeated dosing, respectively. Two different in vivo methods were used: the hollow fiber method with single dosing (i.v. 1.0 mg/kg) and traditional xenografts with repeated dosing over 2 weeks (i.v. 0.5 mg/kg daily, 5 days a week). The human tumor cell lines used displayed dose-dependent in vitro sensitivity (including growth in hollow fibers to confirm passage of cycloviolacin O2 through the polyvinylidene fluoride fibers), with IC50 values in the micromolar range. Despite this sensitivity in vitro, no significant antitumor effects were detected in vivo, neither with single dosing in the hollow fiber method nor with repeated dosing in xenografts. In summary, the results indicate that antitumor effects are minor or absent at tolerable (sublethal) doses, and cycloviolacin O2 has a very abrupt in vivo toxicity profile, with lethality after single injection at 2 mg/kg, but no signs of discomfort to the animals at 1.5 mg/kg. Repeated dosing of 1 mg/kg gave a local-inflammatory reaction at the site of injection after 2–3 days; lower doses were without complications.

  • 18.
    Burman, Robert
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Yeshak, Mariamawit Y.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy. Univ Addis Ababa, Sch Pharm, Dept Pharmacognosy, Addis Ababa, Ethiopia..
    Larsson, Sonny
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Craik, David J.
    Univ Queensland, Inst Mol Biosci, Chem & Struct Biol Div, Craik Lab, Brisbane, Qld, Australia..
    Rosengren, K. Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy. Univ Queensland, Sch Biomed Sci, Lab Peptide Struct Biol, Brisbane, Qld, Australia..
    Göransson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Distribution of circular proteins in plants: large-scale mapping of cyclotides in the Violaceae2015In: Frontiers in Plant Science, ISSN 1664-462X, E-ISSN 1664-462X, Vol. 6, article id 855Article in journal (Refereed)
    Abstract [en]

    During the last decade there has been increasing interest in small circular proteins found in plants of the violet family (Violaceae). These so-called cyclotides consist of a circular chain of approximately 30 amino acids, including six cysteines forming three disulfide bonds, arranged in a cyclic cystine knot (CCK) motif. In this study we map the occurrence and distribution of cyclotides throughout the Violaceae. Plant material was obtained from herbarium sheets containing samples up to 200 years of age. Even the oldest specimens contained cyclotides in the preserved leaves, with no degradation products observable, confirming their place as one of the most stable proteins in nature. Over 200 samples covering 17 of the 23-31 genera in Violaceae were analyzed, and cyclotides were positively identified in 150 species. Each species contained a unique set of between one and 25 cyclotides, with many exclusive to individual plant species. We estimate the number of different cyclotides in the Violaceae to be 5000-25,000, and propose that cyclotides are ubiquitous among all Violaceae species. Twelve new cyclotides from six phylogenetically dispersed genera were sequenced. Furthermore, the first glycosylated derivatives of cyclotides were identified and characterized, further increasing the diversity and complexity of this unique protein family.

  • 19.
    Carstens, Bodil B.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy. Univ Queensland, Inst Mol Biosci, Brisbane, Qld 4072, Australia..
    Rosengren, K. Johan
    Univ Queensland, Sch Biomed Sci, Brisbane, Qld 4072, Australia..
    Gunasekera, Sunithi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Schempp, Stefanie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Bohlin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Dahlstrom, Mia
    SP Tech Res Inst Sweden, Dept Chem Mat & Surfaces, SE-41346 Gothenburg, Sweden..
    Clark, Richard J.
    Univ Queensland, Sch Biomed Sci, Brisbane, Qld 4072, Australia..
    Göransson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Isolation, Characterization, and Synthesis of the Barrettides: Disulfide-Containing Peptides from the Marine Sponge Geodia barretti2015In: Journal of natural products (Print), ISSN 0163-3864, E-ISSN 1520-6025, Vol. 78, no 8, p. 1886-1893Article in journal (Refereed)
    Abstract [en]

    Two disulfide-containing peptides, barrettides A (1) and B (2), from the cold-water marine sponge Geodia barretti are described. Those 31 amino acid residue long peptides were sequenced using mass spectrometry methods and structurally characterized using NMR spectroscopy. The structure of 1 was confirmed by total synthesis using the solid-phase peptide synthesis approach that was developed. The two peptides were found to differ only at a single position in their sequence. The three-dimensional structure of 1 revealed that these peptides possess a unique fold consisting of a long beta-hairpin structure that is cross-braced by two disulfide bonds in a ladder-like arrangement. The peptides are amphipathic in nature with the hydrophobic and charged residues clustered on separate faces of the molecule. The barrettides were found not to inhibit the growth of either Escherichia coli or Staphylococcus aureus but displayed antifouling activity against barnacle larvae (Balanus improvisus) without lethal effects in the concentrations tested.

  • 20.
    Claeson, Per
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Göransson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Johansson, Senia
    Luijendijk, Teus
    Bohlin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Fractionation protocol for the isolation of polypeptides from plant biomass1998In: Journal of natural products (Print), ISSN 0163-3864, E-ISSN 1520-6025, Vol. 61, no 1, p. 77-81Article in journal (Refereed)
    Abstract [en]

    A fractionation protocol for the isolation of a highly purified polypeptide fraction from plant biomass is described. The procedure dereplicates ubiquitous substance classes known to interfere with bioassays often used in natural product-based drug discovery programs. The protocol involves pre-extraction with dichloromethane, extraction with ethanol (50%), removal of tannins with polyamide, removal of low-molecular-weight components with size-exclusion chromatography over Sephadex G-10, and final removal of salts and polysaccharides with solid-phase extraction using reversed-phase cartridges. The method has been applied to the aerial parts of Viola arvensis, resulting in the isolation of a peptide fraction that on further separation yielded a novel 29-residue macrocyclic polypeptide named varv peptide A, cyclo(-TCVGGTCNTPGCSCSWPVCTRNGLPVCGE-).

  • 21.
    Claeson, Per
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Göransson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Johansson, Senia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Luijendijk, Teus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Bohlin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Fractionation protocol for the isolation of polypeptides from plant biomass1998In: Journal of natural products (Print), ISSN 0163-3864, E-ISSN 1520-6025, Vol. 61, no 1, p. 77-81Article in journal (Refereed)
  • 22.
    Craik, David J.
    et al.
    Univ Queensland, Inst Mol Biosci, Div Chem & Struct Biol, Brisbane, Qld 4072, Australia..
    Shim, Youn Young
    Univ Saskatchewan, Coll Agr & Bioresources, Dept Plant Sci, 51 Campus Dr, Saskatoon, SK S7N 5A8, Canada.;Prairie Tide Chem Inc, 102 Melville St, Saskatoon, SK S7J 0R1 5A8, Canada.;Jinan Univ, Dept Food Sci & Engn, Guangdong Saskatchewan Oilseed Joint Lab, 601 Huangpu Ave West, Guangzhou 510632, Guangdong, Peoples R China..
    Göransson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Moss, Gerard P.
    Queen Mary Univ London, Sch Biol & Chem Sci, Mile End Rd, London E1 4NS, England..
    Tan, Ninghua
    China Pharmaceut Univ, Sch Tradit Chinese Med, 639 Longmian Ave, Nanjing 211198, Jiangsu, Peoples R China..
    Jadhav, Pramodkumar D.
    Univ Saskatchewan, Coll Agr & Bioresources, Dept Plant Sci, 51 Campus Dr, Saskatoon, SK S7N 5A8, Canada..
    Shen, Jianheng
    Univ Saskatchewan, Coll Agr & Bioresources, Dept Plant Sci, 51 Campus Dr, Saskatoon, SK S7N 5A8, Canada..
    Reaney, Martin J. T.
    Univ Saskatchewan, Coll Agr & Bioresources, Dept Plant Sci, 51 Campus Dr, Saskatoon, SK S7N 5A8, Canada.;Prairie Tide Chem Inc, 102 Melville St, Saskatoon, SK S7J 0R1 5A8, Canada.;Jinan Univ, Dept Food Sci & Engn, Guangdong Saskatchewan Oilseed Joint Lab, 601 Huangpu Ave West, Guangzhou 510632, Guangdong, Peoples R China..
    Nomenclature of homodetic cyclic peptides produced from ribosomal precursors: An IUPAC task group interim report2016In: Biopolymers, ISSN 0006-3525, E-ISSN 1097-0282, Vol. 106, no 6, p. 917-924Article in journal (Refereed)
    Abstract [en]

    In 2015, an International Union of Pure and Applied Chemistry (IUPAC) Task Group was formed to develop nomenclature recommendations for homodetic cyclic peptides produced from ribosomal precursors. Delegates of the 2015 International Conference on Circular Proteins (ICCP) were presented with the strengths and weaknesses of four published approaches to homodetic cyclic peptide nomenclature, and a summary of the ensuing discussion is presented here. This interim report presents a potentially novel suggestion-the use of Cahn-Ingold-Prelog rules to specify amino acid priority in homodetic peptides for consistent numbering. Indeed, this might be the first extension of the Cahn-Ingold-Prelog rules in five decades. The authors invite interested parties to contact the corresponding author with suggestions for the improvement of the proposed nomenclature; these ideas will be discussed and considered for inclusion in the final report.

  • 23. Dahlström, Mia
    et al.
    Sjögren, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Jonsson, Per R.
    Göransson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Lindh, Liselott
    Arnebrant, Thomas
    Pinori, Emiliano
    Elwing, Hans
    Berglin, Mattias
    Affinity states of biocides determine bioavailability and release rates in marine paints2015In: Biofouling (Print), ISSN 0892-7014, E-ISSN 1029-2454, Vol. 31, no 2, p. 201-210Article in journal (Refereed)
    Abstract [en]

    A challenge for the next generation marine antifouling (AF) paints is to deliver minimum amounts of biocides to the environment. The candidate AF compound medetomidine is here shown to be released at very low concentrations, ie ng ml(-1) day(-1). Moreover, the release rate of medetomidine differs substantially depending on the formulation of the paint, while inhibition of barnacle settlement is independent of release to the ambient water, ie the paint with the lowest release rate was the most effective in impeding barnacle colonisation. This highlights the critical role of chemical interactions between biocide, paint carrier and the solid/aqueous interface for release rate and AF performance. The results are discussed in the light of differential affinity states of the biocide, predicting AF activity in terms of a high surface affinity and preserved bioavailability. This may offer a general framework for the design of low-release paint systems using biocides for protection against biofouling on marine surfaces.

  • 24.
    Demma, Jemal
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    El-Seedi, Hesham
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Engidawork, Ephrem
    Aboye, Teshome Leta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Göransson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Hellman, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    An in vitro Study on the DNA Damaging Effects of Phytochemicals Partially Isolated from an Extract of Glinus lotoides2013In: Phytotherapy Research, ISSN 0951-418X, E-ISSN 1099-1573, Vol. 27, no 4, p. 507-514Article in journal (Refereed)
    Abstract [en]

    An extract of Glinus lotoides, a medicinal plant used in Africa and Asia for various therapeutic purposes, was recently shown to cause DNA damage in vitro. To further explore the potential genotoxicity of this plant, fractionation of the crude extract was performed using reverse phase solid-phase extraction and a stepwise gradient elution of methanol in water. Four fractions were collected and subsequently analysed for their DNA damaging effects in mouse lymphoma cells using an alkaline version of the comet assay. To identify potential genotoxic and non-genotoxic principles, each fraction was then subjected to liquid chromatography coupled to mass spectrometry, LC-MS/MS. 1D and 2D nuclear magnetic resonance analyses were used to confirm the identity of some saponins. Although fractions containing a mixture of flavonoids and oleanane-type saponins or oleanane-type saponins alone produced no DNA damage, those containing hopane-type saponins exhibited a pronounced DNA damaging effect without affecting the viability of the cells. To conclude, even if this study presents evidence that hopane-type of saponins are endowed with a DNA damaging ability, further studies are needed before individual saponins can be cited as a culprit for the previously reported genotoxicity of the crude extract of G. lotoides.

  • 25.
    El-Seedi, Hesham
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    El-Said, A. M. A.
    Khalifa, S. A. M.
    Göransson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Bohlin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Borg-Karlson, A. -K
    Verpoorte, R.
    Biosynthesis, natural sources, dietary intake, pharmacokinetic properties, and biological activities of hydroxycinnamic acids2012In: Journal of Agricultural and Food Chemistry, ISSN 0021-8561, E-ISSN 1520-5118, Vol. 60, no 44, p. 10877-10895Article, review/survey (Refereed)
    Abstract [en]

    Hydroxycinnamic acids are the most widely distributed phenolic acids in plants. Broadly speaking, they can be defined as compounds derived from cinnamic acid. They are present at high concentrations in many food products, including fruits, vegetables, tea, cocoa, and wine. A diet rich in hydroxycinnamic acids is thought to be associated with beneficial health effects such as a reduced risk of cardiovascular disease. The impact of hydroxycinnamic acids on health depends on their intake and pharmacokinetic properties. This review discusses their chemistry, biosynthesis, natural sources, dietary intake, and pharmacokinetic properties.

  • 26.
    El-Seedi, Hesham R.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Burman, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Mansour, Ahmed
    Turki, Zaki
    Boulos, Loutfy
    Gullbo, Joachim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Göransson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    The traditional medical uses and cytotoxic activities of sixty-one Egyptian plants: Discovery of an active cardiac glycoside from Urginea maritima2013In: Journal of Ethnopharmacology, ISSN 0378-8741, E-ISSN 1872-7573, Vol. 145, no 3, p. 746-757Article in journal (Refereed)
    Abstract [en]

    Ethnopharmacological relevance: Medicinal plants from the Sinai desert are widely used in traditional Bedouin medicine to treat a range of conditions including, cancers, and may thus be useful sources of novel anti-tumor compounds. Information on plants used in this way was obtained through collaboration with Bedouin herbalists. Aim of the study: To document the traditional uses of 61 species from 29 families of Egyptian medicinal plants and to investigate their biological activity using a cytotoxicity assay. Material and methods: MeOH extracts of the 61 plant species investigated were dissolved in 10% DMSO and their cytotoxic activity was evaluated. The extracts were tested in duplicate on three separate occasions at three different concentrations (1, 10 and 100 mu g/ml) against human lymphoma U-937 GTB. The most active extract was subjected to bioassay-guided fractionation using HPLC and LC/ESI-MS to isolate and identify its active components. Results and discussion: The most potent extracts were those from Asclepias sinaica, Urginea maritima, Nerium oleander and Catharanthus roseus, followed by those from Cichorium endivia, Pulicaria undulate and Melia azedarach. Literature reports indicate that several of these plants produce cardiac glycosides. Bioassay-guided fractionation of alcoholic U. maritima extracts led to the isolation of a bioactive bufadienolide that was subsequently shown to be proscillaridin A, as determined by 1D and 2D NMR spectroscopy. This result demonstrates the value of plants used in traditional medicine as sources of medicinally interesting cytotoxic compounds.

  • 27.
    El-Seedi, Hesham R.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    El-Barbary, M. A.
    El-Ghorab, D. M. H.
    Bohlin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Borg-Karlson, Anna-Karin
    Göransson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Verpoorte, R.
    Recent insights into the biosynthesis and biological activities of natural xanthones2010In: Current Medicinal Chemistry, ISSN 0929-8673, E-ISSN 1875-533X, Vol. 17, no 9, p. 854-901Article, review/survey (Refereed)
    Abstract [en]

    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.

  • 28.
    El-Seedi, Hesham R.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    El-Ghorab, Dina M H
    El-Barbary, Mai A
    Zayed, Mervat F
    Göransson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Larsson, Sonny
    Verpoorte, Rob
    Naturally occurring xanthones; latest investigations: isolation, structure elucidation and chemosystematic significance2009In: Current Medicinal Chemistry, ISSN 0929-8673, E-ISSN 1875-533X, Vol. 16, no 20, p. 2581-2626Article, review/survey (Refereed)
    Abstract [en]

    In this review, an updated literature survey covering the reports of naturally occurring xanthones in the period of 2005-2008 is presented. In some 143 studies, the isolation of 264 different xanthones from 36 plant species (representing 15 genera in 6 families of higher plants), 7 species of fungi, and 1 lichen species were reported. Of these, 122 compounds were isolated for the first time from nature. We discuss plant origin, the way of separation, and spectral analysis done for structure elucidation, along with a brief discussion of the chemosystematic significance.

  • 29.
    El-Seedi, Hesham R.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    El-Shabasy, Rehan
    Sakr, Hanem
    Zayed, Mervat
    El-Said, Asmaa M. A.
    Helmy, Khalid M. H.
    Gaara, Ahmed H. M.
    Turki, Zaki
    Azeem, Muhammad
    Ahmed, Ahmed M.
    Boulos, Loutfy
    Borg-Karlson, Anna-Karin
    Göransson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Anti-schistosomiasis triterpene glycoside from the Egyptian medicinal plant Asparagus stipularis2012In: Revista Brasileira de Farmacognosia, ISSN 0102-695X, Vol. 22, no 2, p. 314-318Article in journal (Refereed)
    Abstract [en]

    Bioassay-guided isolation using an in vitro assay testing for anti-schistosomiasis yielded a novel triterpene saponin, asparagalin A, from the n-butanol extract of the roots of Asparagus stipularis Forssk., Asparagaceae. The structure was elucidated by spectroscopic analysis and chemical transformations. Administration of asparagalin A resulted in a retardation of worm growth and locomotion at the first day and showed a significant activity of egg-laying suppression at 200 mu g/mL concentration.

  • 30.
    El-Seedi, Hesham R.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Khalil, Nasr S.
    Azeem, Muhammad
    Taher, Eman A.
    Göransson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Palsson, Katinka
    Borg-Karlson, Anna-Karin
    Chemical Composition and Repellency of Essential Oils From Four Medicinal Plants Against Ixodes ricinus Nymphs (Acari Ixodidae)2012In: Journal of medical entomology, ISSN 0022-2585, E-ISSN 1938-2928, Vol. 49, no 5, p. 1067-1075Article in journal (Refereed)
    Abstract [en]

    In our search for effective tick repellents from plant origin, we investigated the effect of essential oils of four medicinal and culinary plants belonging to the family Lamiaceae on nymphs of the tick Ixodes ricinus (L.). The essential oils of the dry leaves of Rosmarinus officinalis (Rosemary) (L.), Mentha spicata (Spearmint) (L.), Origanum majorana (Majoram) (L.), and Ocimum basilicum (Basil) (L.) were isolated by steam distillation and 15 mu g/cm(2) concentration of oils was tested against ticks in a laboratory bioassay. The oils of R. officinalis, M. spicata, and O. majorana showed strong repellency against the ticks 100, 93.2, and 84.3%, respectively, whereas O. basilicum only showed 64.5% repellency. When tested in the field, the oils of R. officinalis and M. spicata showed 68.3 and 59.4% repellency at a concentration of 6.5 mu g/cm(2) on the test cloths. The oils were analyzed by gas chromatography mass spectrometry and the major compounds from the most repellent oils were 1,8-cineole, camphor, linalool, 4-terpineol, borneol, and carvone.

  • 31. Fernandes-Cerqueira, Catia
    et al.
    Ossipova, Elena
    Gunasekera, Sunithi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Hansson, Monika
    Mathsson, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Catrina, Anca I.
    Sommarin, Yngve
    Klareskog, Lars
    Lundberg, Karin
    Rönnelid, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Göransson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Jakobsson, Per-Johan
    Targeting of anti-citrullinated protein/peptide antibodies in rheumatoid arthritis using peptides mimicking endogenously citrullinated fibrinogen antigens2015In: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 17, article id 155Article in journal (Refereed)
    Abstract [en]

    Introduction: We have previously identified endogenously citrullinated peptides derived from fibrinogen in rheumatoid arthritis (RA) synovial tissues. In this study, we have investigated the auto-antigenicity of four of those citrullinated peptides, and explored their feasibility to target anti-citrullinated protein/peptide antibodies (ACPA). Methods: The autoantigenic potential of the fibrinogen peptides was investigated by screening 927 serum samples from the Epidemiological Investigation of RA (EIRA) cohort on a peptide microarray based on the ImmunoCAP ISAC (R) system. In order to assay for ACPA blocking, two independent pools of purified ACPA were incubated with the respective targeting peptide prior to binding to cyclic citrullinated peptide (CCP) 2 using the CCPlus (R) ELISA kit. Results: Two peptides derived from the fibrinogen a chain, Arg573Cit (563-583) and Arg591Cit (580-600), referred to as Cit573 and Cit591, and two peptides from the fibrinogen beta chain, Arg72Cit (62-81) and Arg74Cit (62-81) (Cit72 and Cit74), displayed 65 %, 15 %, 35 %, and 53 % of immune reactivity among CCP2-positive RA sera, respectively. In CCP2-negative RA sera, a positive reactivity was detected in 5 % (Cit573), 6 % (Cit591), 8 % (Cit72), and 4 % (Cit74). In the competition assay, Cit573 and Cit591 peptides reduced ACPA binding to CCP2 by a maximum of 84 % and 63 % respectively. An additive effect was observed when these peptides were combined. In contrast, Cit74 and Cit72 were less effective. Cyclization of the peptide structure containing Cit573 significantly increased the blocking efficiency. Conclusions: Here we demonstrate extensive autoantibody reactivity against in vivo citrullinated fibrinogen epitopes, and further show the potential use of these peptides for antagonizing ACPA.

  • 32. Gerlach, Samantha L.
    et al.
    Burman, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Bohlin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Mondal, Debasis
    Göransson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Isolation, Characterization, and Bioactivity of Cyclotides from the Micronesian Plant Psychotria leptothyrsa2010In: Journal of natural products (Print), ISSN 0163-3864, E-ISSN 1520-6025, Vol. 73, no 7, p. 1207-1213Article in journal (Refereed)
    Abstract [en]

    Cyclotides, the largest known family of head-to-tail cyclic peptides, have approximately 30 amino acid residues with a complex structure containing a circular peptide backbone and a cystine knot. They are found in plants from the Violaceae and Rubiaceae families and are speculated to function in plant protection. In addition to their insecticidal properties, cyclotides display cytotoxic. anti-IIIV, antimicrobial, and inhibition of neurotensin binding activities. Although cyclotides are present in all violaceous species hitherto screened, their distribution and expression in Rubiaceae are not fully understood. In this study, we show that Psychotria leptothyrsa var. longicarpa (Rubiaceae) contains a suite of different cyclotides. The cyclotide fractions were isolated by RP-HPLC, and sequences of six new peptides, named psyles A-F. were determined by MS/MS sequencing. One or these, psyle C. is the first rubiaceous linear variant known. Psyles A, C, and E were analyzed in a fluorometric microculture assay to determine cytotoxicity toward the human lymphoma cell line U937-GTB. The IC50 values of psylcs A. C. and E were 26, 3.50, and 0.76 mu M. respectively. This study expands the number of known rubiaceous cyclotides and shows that the linear cyclotide maintains cytotoxicity.

  • 33. Gerlach, Samantha L.
    et al.
    Göransson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Kaas, Quentin
    Craik, David J.
    Mondal, Debasis
    Gruber, Christian W.
    A Systematic Approach to Document Cyclotide Distribution in Plant Species from Genomic, Transcriptomic, and Peptidomic Analysis2013In: Biopolymers, ISSN 0006-3525, E-ISSN 1097-0282, Vol. 100, no 5, p. 433-437Article in journal (Refereed)
    Abstract [en]

    Cyclotides are a large family of plant peptides characterized by their cyclic cystine knot composed of a circular backbone and three disulfide bonds that impart exceptional stability. They, and several acyclic variants, have been isolated from plants within the Rubiaceae, Violaceae, Cucurbitaceae, Fabaceae, Solanaceae, and Poaceae families. A variety of chemical and genetic approaches have been applied for the discovery and characterization of cyclotides. As investigations of cyclotide expression, distribution, and phylogeny rapidly increase, the authors have proposed the inclusion of information pertaining to plant species that have been analyzed but do not appear to express cyclotides into the CyBase database. CyBase is dedicated to providing web tools and information about cyclic peptides and proteins to the scientific community. Including detailed information about sampling and analysis parameters of plant species that have been investigated but not published elsewhere should assist in the process of selecting species for establishing new cyclotide discovery projects, as well as for detailed reanalysis using alternative technical approaches. In summary, the collection and deposition of all plant species that have been examined (whether cyclotides have been found or not) would help to impart a deeper understanding of cyclotide discovery, evolution, and physiological function.

  • 34. Gerlach, Samantha L.
    et al.
    Rathinakumar, Ramesh
    Chakravarty, Geetika
    Göransson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Wimley, William C.
    Darwin, Steven P.
    Mondal, Debasis
    Anticancer and Chemosensitizing Abilities of Cycloviolacin O2 from Viola odorata and Psyle Cyclotides from Psychotria leptothyrsa2010In: Biopolymers, ISSN 0006-3525, E-ISSN 1097-0282, Vol. 94, no 5, p. 617-625Article in journal (Refereed)
    Abstract [en]

    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 mu M) were monitored in the presence and absence of doxorubicin (0.1-5 mu M) using cell proliferation assays to establish its chemosensitizing abilities. SYTOX Green assays were performed to verify membrane permeabilization and showed cellular disruption correlates with cyclo tide 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 cyclo tide 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 mu M), and coexposure to cyclotides significantly enhanced doxorubicin induced toxicity (IC50 = 0.39-0.76 mu M). This study documents several cyclotides with robust cytotoxicity that may be promising chemosensitizing agents against drug resistant breast cancer.

  • 35. Gerlach, Samantha L.
    et al.
    Yeshak, Mariamawit
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Göransson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Roy, Upal
    Izadpanah, Reza
    Mondal, Debasis
    Cycloviolacin O2 (CyO2) Suppresses Productive Infection and Augments the Antiviral Efficacy of Nelfinavir in HIV-1 Infected Monocytic Cells2013In: Biopolymers, ISSN 0006-3525, E-ISSN 1097-0282, Vol. 100, no 5, p. 471-479Article in journal (Refereed)
    Abstract [en]

    Human immunodeficiency virus type-1 (HIV-1), the etiologic agent of acquired immune deficiency syndrome (AIDS), is a global pandemic causing millions of deaths annually. Highly active antiretroviral therapy (HAART) greatly enhances lifespan but eventually causes debilitating side effects, in part, due to their chronic administration required to suppress HIV-1 replication. If treatment is discontinued, viral suppression is lost and dormant replication-competent monocytic cell reservoirs become reactivated, leading to viral recrudescence and progression to AIDS. Therefore, novel strategies to circumvent obstacles to HIV-1 therapy are critically needed. We evaluated the potentially therapeutic effects of cycloviolacin O2 (CyO2) on cell viability (MTTassay), membrane disruption (SYTOX Green uptake), p24 production [enzyme-linked immunosorbent assays (ELISA)], and proviral integration (PCR amplification) in U1 cells; a monocytic cell model of HIV-1 latency and reactivation. We demonstrate, for the first time, that CyO2 (0.5-5.0 mu M) kills productively infected cells. Sub-toxic concentrations (< 0.5 mu M) of CyO2 disrupted plasma membranes in both latently-infected and productively-infected U1 cells and enhanced the antiviral efficacy of nelfinavir, a HIV-1 protease inhibitor (HPI). Interestingly, CyO2 also decreased virus production by activated U1 cells; however, this effect was not due to suppression of integrated provirus in U1 cells. This suggested that, in addition to the known pore-forming ability of cyclotides, a novel mode of antiviral activity may exist for CyO2. Our data indicate that CyO2 may be a promising candidate for the targeting HIV-1 reservoirs in monocytes, and their inclusion in adjuvant therapy approaches may augment the efficacy of HPIs and ultimately facilitate virus elimination.

  • 36. Gruber, Christian W
    et al.
    Elliott, Alysha G
    Ireland, David C
    Delprete, Piero G
    Dessein, Steven
    Göransson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Trabi, Manuela
    Wang, Conan K
    Kinghorn, Andrew B
    Robbrecht, Elmar
    Craik, David J
    Distribution and evolution of circular miniproteins in flowering plants2008In: The Plant Cell, ISSN 1040-4651, E-ISSN 1532-298X, Vol. 20, no 9, p. 2471-2483Article in journal (Refereed)
    Abstract [en]

    Cyclotides are disulfide-rich miniproteins with the unique structural features of a circular backbone and knotted arrangement of three conserved disulfide bonds. Cyclotides have been found only in two plant families: in every analyzed species of the violet family (Violaceae) and in few species of the coffee family (Rubiaceae). In this study, we analyzed >200 Rubiaceae species and confirmed the presence of cyclotides in 22 species. Additionally, we analyzed >140 species in related plant families to Rubiaceae and Violaceae and report the occurrence of cyclotides in the Apocynaceae. We further report new cyclotide sequences that provide insights into the mechanistic basis of cyclotide evolution. On the basis of the phylogeny of cyclotide-bearing plants and the analysis of cyclotide precursor gene sequences, we hypothesize that cyclotide evolution occurred independently in various plant families after the divergence of Asterids and Rosids ( approximately 125 million years ago). This is strongly supported by recent findings on the in planta biosynthesis of cyclotides, which involves the serendipitous recruitment of ubiquitous proteolytic enzymes for cyclization. We further predict that the number of cyclotides within the Rubiaceae may exceed tens of thousands, potentially making cyclotides one of the largest protein families in the plant kingdom.

  • 37.
    Gunasekera, Sunithi
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Aboye, Teshome L.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Madian, Walid A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    El-Seedi, Hesham R.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Göransson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Making Ends Meet: Microwave-Accelerated Synthesis of Cyclic and Disulfide Rich Proteins Via In Situ Thioesterification and Native Chemical Ligation2013In: International Journal of Peptide Research and Therapeutics, ISSN 1573-3149, Vol. 19, no 1- SI, p. 43-54Article in journal (Refereed)
    Abstract [en]

    The development of synthetic methodologies for cyclic peptides is driven by the discovery of cyclic peptide drug scaffolds such as the plant-derived cyclotides, sunflower trypsin inhibitor 1 (SFTI-1) and the development of cyclized conotoxins. Currently, the native chemical ligation reaction between an N-terminal cysteine and C-terminal thioester group remains the most robust method to obtain a head-to-tail cyclized peptide. Peptidyl thioesters are effectively generated by Boc SPPS. However, their generation is challenging using Fmoc SPPS because thioester linkers are not stable to repeated piperidine exposure during deprotection. Herein we describe a Fmoc-based protocol for synthesizing cyclic peptides adapted for microwave assisted solid phase peptide synthesis. The protocol relies on the linker Di-Fmoc-3,4-diaminobenzoic acid, and we demonstrate the use of Gly, Ser, Arg and Ile as C-terminal amino acids (using HBTU and HATU as coupling reagents). Following synthesis, an N-acylurea moiety is generated at the C-terminal of the peptide; the resin bound acylurea peptide is then deprotected and cleaved from the resin. The fully deprotected peptide undergoes thiolysis in aqueous buffer, generating the thioester in situ. Ultimately, the head-to-tail cyclized peptide is obtained via native chemical ligation. Two naturally occurring cyclic peptides, the prototypical Mobius cyclotide kalata B1 and SFTI-1 were synthesized efficiently, avoiding potential branching at the diamino linker, using the optimized protocol. In addition, we demonstrate the possibility to use the approach for the synthesis of long and synthetically challenging linear sequences, by the ligation of two truncated fragments of a 50-residue long plant defensin.

  • 38.
    Gunasekera, Sunithi
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Fernandes-Cerqueira, C.
    Karolinska Inst, Rheumatol Unit, Dept Med, Stockholm, Sweden..
    Eriksson, Camilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Jakobsson, P-J
    Göransson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Anti-Citrullinated Peptide Antibody Inhibitors Based On Sunflower Trypsin Inhibitor-1 Scaffold For Potential Anti-Rheumatoid Arthritis Activity2016In: Journal of Peptide Science, ISSN 1075-2617, E-ISSN 1099-1387, Vol. 22, no S2, p. S170-S170Article in journal (Other academic)
  • 39.
    Gunasekera, Sunithi
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Göransson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Fmoc-SPPS based synthesis of bioactive cyclic peptides via N-acylurea intermediates2012In: Journal of Peptide Science, ISSN 1075-2617, E-ISSN 1099-1387, Vol. 18, no suppl 1, p. S182-S182Article in journal (Other academic)
    Abstract [en]

    The plant cyclotides form the largest family of cyclic peptides(1). They contain a signature motif referred to as the cyclic cystine knot, which is derived from the cyclic backbone and three inter-knotted disulfide bonds. Intriguingly, cyclotides can be boiled, treated with chemicals or enzymes without disrupting their overall fold. Thus, they are sometimes labeled as ultra-stable proteins. In addition, cyclotides are tolerant to mutations, and as a scaffold they can successfully accommodate foreign bioactive epitopes of variable sequences(2). Cyclotides share many of these properties with another disulfide containing cyclic plant peptide, the sunflower trypsin inhibitor 1 (SFTI-1)(3). Emerging evidence indicates that cyclotides and SFTI-1 are valuable not only as peptide stabilizing scaffolds; in combination with their cell penetrating properties, these disulfide rich cyclic peptides have significance as intracellular drug carriers. Although both peptides are genetically encoded, studies to ascertain the exact mechanisms of their biosynthesis are currently on going. Thus, the synthesis of cyclotides and SFTI-1 are currently restricted to chemical means. We have recently adapted a Fmoc-SPPS method for cyclic peptide synthesis, via N-acylurea intermediates with the assistance of microwave irradiation.

    This method is a safe and convenient alternative to Boc-SPPS and has the ability to be automated conveniently. Using this method, parent scaffolds as well as several cyclotide and SFTI-1 analogues with potential antimicrobial and matrix metalloprotease activities were synthesized. With the rising interest in the cyclization concept as a tool to impart stability on unstable peptides, the cyclic peptide synthesis method adapted herein is anticipated to have numerous applications.

    1. Burman, R.; Gunasekera, S.; Stromstedt, A.; Rosengren, J.; Goransson, U. J. Biol. Chem. 2012 (in press)

    2. Gunasekera, S.; Foley, F. M.; Clark, R. J.; Sando, L.; Fabri, L. J.; Craik, D. J.; Daly, N. L. J. Med. Chem. 2008, 51, 7697.

    3. Chan, L. Y.; Gunasekera, S.; Henriques, S. T.; Worth, N. F.; Le, S. J.; Clark, R. J.; Campbell, J. H.; Craik, D. J.; Daly, N. L. Blood 2011, 118, 6709.

  • 40.
    Gunasekera, Sunithi
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Muhammad, Taj
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Strömstedt, Adam A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Göransson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Backbone-Cyclized Peptide Dimers Derived from Human Cathelicidin Peptide LL-37 Mediate Potent Antimicrobial Activity2014In: Journal of Peptide Science, ISSN 1075-2617, E-ISSN 1099-1387, Vol. 20, p. S270-S271Article in journal (Other academic)
  • 41.
    Göransson, Ulf
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Broussalis, Adriana M
    Claeson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Expression of Viola cyclotides by liquid chromatography-mass spectrometry and tandem mass spectrometry sequencing of intercysteine loops after introduction of charges and cleavage sites by aminoethylation2003In: Analytical Biochemistry, ISSN 0003-2697, E-ISSN 1096-0309, Vol. 318, no 1, p. 107-117Article in journal (Refereed)
    Abstract [en]

    The expression of cyclotides—macrocyclic plant peptides—was profiled in six violets, Viola cotyledon, V. biflora, V. arvensis,V. tricolor, V. riviniana, and V. odorata, by LC-MS. All were found to express notably complex mixtures, with single speciescontaining >50 cyclotides. To facilitate their sequencing by MS-MS, an analytical strategy is presented involving aminoethylation ofcysteines. This overcomes a number of problems intimately associated with the cyclotide core structure—that is, their joined N and Ctermini, disulfide knot, and low or clustered content of positively charged amino acids and enzymatic cleavage sites. As a result,charges as well as cleavage sites are introduced at the most conserved part of their sequence, the cysteines. Combined with trypticdigestion, all intercysteine loops are then of suitable size and charge for MS-MS sequencing. The utility of this strategy is shown bythe sequencing of two novel cyclotides isolated from V. cotyledon; vico A (cyclo-(AESCVYIPCFTGIAGCSCKNKVCYYNGSIPC)) and vico B(cyclo-(AESCVYIPCITGIAGCSCKNKVCYYNGSIPC)); their complete sequence could be determined bynanospray MS-MS. The strategy for converting conserved cysteines to enzymatic cleavage sites might also benefit the study of otherpeptides and proteins displaying similar structural problems for MS analysis.

  • 42.
    Göransson, Ulf
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Burman, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Gunasekera, Sunithi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Strömstedt, Adam A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Rosengren, K. Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Circular Proteins from Plants and Fungi2012In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 287, no 32, p. 27001-27006Article, review/survey (Refereed)
    Abstract [en]

    Circular proteins, defined as head-to-tail cyclized polypeptides originating from ribosomal synthesis, represent a novel class of natural products attracting increasing interest. From a scientific point of view, these compounds raise questions of where and why they occur in nature and how they are formed. From a rational point of view, these proteins and their structural concept may be exploited for crop protection and novel pharmaceuticals. Here, we review the current knowledge of three protein families: cyclotides and circular sunflower trypsin inhibitors from the kingdom of plants and the Amanita toxins from fungi. A particular emphasis is placed on their biological origin, structure, and activity. In addition, the opportunity for discovery of novel circular proteins and recent insights into their mechanism of action are discussed.

  • 43.
    Göransson, Ulf
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Craik, David J
    Disulfide mapping of the cyclotide kalata B1: Chemical proof of the cystic cystine knot motif2003In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 278, no 48, p. 48188-48196Article in journal (Refereed)
    Abstract [en]

    The cyclotides are a recently discovered family of plant proteins that have the fascinating structural feature of a continuous cyclic backbone and, putatively, a knotted arrangement of their three conserved disulfide bonds. We here show definite chemical proof of the I-IV, II-V, III-VI knotted disulfide connectivity of the prototypic cyclotide kalata B1. This has been achieved by a new approach for disulfide analysis, involving partial reduction and stepwise alkylation including introduction of charges and enzymatic cleavage sites by aminoethylation of cysteines. The approach overcomes the intrinsic difficulties for disulfide mapping of cyclotides, i.e. the cyclic amide backbone, lack of cleavage sites between cysteines, and a low or clustered content of basic amino acids, and allowed a direct determination of the disulfide bonds in kalata B1 using analysis by mass spectrometry. The established disulfide connectivity is unequivocally shown to be cystine knotted by a topological analysis. This is the first direct chemical determination of disulfides in native cyclotides and unambiguously confirms the unique cyclic cystine knot motif.

  • 44.
    Göransson, Ulf
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Herrmann, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Burman, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Haugaard-Jonsson, M
    Rosengren, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    The Conserved Glu in the Cyclotide Cycloviolacin O2 Has a Key Structural Role2009In: ChemBioChem (Print), ISSN 1439-4227, E-ISSN 1439-7633, Vol. 10, no 14, p. 2354-2360Article in journal (Refereed)
    Abstract [en]

    Cyclotides are a large family of plant peptides that are characterised by a head-to-tail circular backbone and three disulfide bonds that are arranged in a cystine knot. This unique structural feature, which is referred to as a cyclic cystine knot, gives the cyclotides remarkable stability against chemical and biological degradation. In addition to their natural function as insecticides for plant defence, the cyclotides have a range of bioactivities with pharmaceutical relevance, including cytotoxicity against cancer cell lines. A glutamic acid residue, aside from the invariable disulfide array, is the most conserved feature throughout the cyclotide family, and it has recently been shown to be crucial for biological activity. Here we have used solution-state NMR spectroscopy to determine the three-dimensional structures of the potent cytotoxic cyclotide cycloviolacin O2, and an inactive analogue in which this conserved glutamic acid has been methylated. The structures of the peptides show that the glutamic acid has a key structural role in coordinating a set of hydrogen bonds in native cycloviolacin O2; this interaction is disrupted in the methylated analogue. The proposed mechanism of action of cyclotides is membrane disruption and these results suggest that the glutamic acid is linked to cyclotide function by stabilising the structure to allow efficient aggregation in membranes, rather than in a direct interaction with a target receptor.

  • 45.
    Göransson, Ulf
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Luijendijk, Teus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Johansson, Senia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Bohlin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Claeson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Seven novel macrocyclic polypeptides from Viola arvensis1999In: Journal of natural products (Print), ISSN 0163-3864, E-ISSN 1520-6025, Vol. 62, no 2, p. 283-286Article in journal (Refereed)
    Abstract [en]

    Seven novel macrocyclic polypeptides, designated as varv peptides B-H, have been isolated from the aerial parts of Viola arvensis. Their primary structures have been elucidated by automated Edman degradation and mass spectrometry. They all consist of 29 or 30 amino acid residues, covalently cyclized via the amide backbone and by three internal disulfide bridges. Their amino acid sequences are as follows: varv peptide B, cyclo-(TCFGGTCNTPGCSCDPWPMCSRNGLPVCGE); varv peptide C, cyclo-(TCVGGTCNTPGCSCSWPVCTRNGVPICGE); varv peptide D, cyclo-(TCVGGSCNTPGCSCSWPVCTRNGLPICGE); varv peptide E, cyclo-(TCVGGTCNTPGCSCSWPVCTRNGLPICGE); varv peptide F, cyclo-(TCTLGTCYTAGCSCSWPVCTRNGVPICGE); varv peptide G, cyclo-(TCFGGTCNTPGCSCDPWPVCSRNGVPVCGE); and varv peptide H, cyclo-(TCFGGTCNTPGCSCETWPVCSRNGLPVCGE). The varv peptides B-H exhibited high degrees of homology with the hitherto known macrocyclic peptides varv peptide A, kalata B1, violapeptide I, circulins A and B, and cyclopsychotride A.

  • 46.
    Göransson, Ulf
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Malik, Sohaib
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Slazak, Blazej
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy. W.SZAFER INSTITUTE OF BOTANY OF THE POLISH ACADEMY OF SCIENCES.
    Cyclotides in the Violaceae2015In: Plant Cyclotides / [ed] Craik, David J., Academic Press , 2015, Vol. 76, p. 15-49Chapter in book (Other academic)
    Abstract [en]

    Abstract It has been 20 years since the cyclic cystine-knotted compounds, called cyclotides, tied our knot with the violets. This chapter, above all, is a lucid summary of the twists, turns, knots, and rings in the relationship that followed. The chapter begins by giving an account of how a little known scientific article facilitated the discovery of cyclotides in Violaceae, how it captured our imagination, and how it was realized that the discovery of a series of cyclotides was within a touching distance. The processes of extraction, isolation, and characterization as well as chemical synthesis of cyclotides used in our laboratory have been described, and in doing so, the solvents, materials, conditions, instrumentation, and techniques involved have been pointed out. An introduction to Violaceae and a description of these plants in diverse cultural settings for various therapeutic purposes is provided. A section follows it on the discovery of cycloviolacin O2 from Viola odorata as a potent antimicrobial peptide, and how its interaction with bacteria in terms of mechanism of action and resistance development was investigated. It is followed by a reflection on how the recent innovations in biotechnology and bioinformatics have helped out along the way: the use of novel strategies for cyclization and the use of transcriptomics data in the discovery of new cyclotides. Finally, the question about biological role of cyclotides in Violaceae has been asked, and an attempt to answer this question has been presented.

  • 47.
    Göransson, Ulf
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Sjögren, Martin
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Svangård, Erika
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Claeson, Per
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Bohlin, Lars
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Reversible Antifouling Effect of the Cyclotide Cycloviolacin O2 against Barnacles.2004In: J Nat Prod, ISSN 0163-3864, Vol. 67, no 8, p. 1287-90Article in journal (Refereed)
  • 48.
    Göransson, Ulf
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Svangård, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Claeson, Per
    Bohlin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Novel strategies for isolation and characterization of cyclotides: the discovery of bioactive macrocyclic plant polypeptides in the Violaceae2004In: Current protein and peptide science, ISSN 1389-2037, E-ISSN 1875-5550, Vol. 5, no 5, p. 317-29Article in journal (Refereed)
  • 49.
    Hedner, Erik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Sjögren, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Frändberg, Per-Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Biological Research on Drug Dependence.
    Johansson, Tobias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Biological Research on Drug Dependence.
    Göransson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Dahlström, Mia
    Jonsson, Per R.
    Nyberg, Fred
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Biological Research on Drug Dependence.
    Bohlin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Brominated cyclodipeptides from the marine sponge Geodia barretti as selective 5-HT ligands2006In: Journal of natural products (Print), ISSN 0163-3864, E-ISSN 1520-6025, Vol. 69, no 10, p. 1421-1424Article in journal (Refereed)
    Abstract [en]

    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.

  • 50.
    Hedner, Erik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Sjögren, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Hodzic, Said
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Andersson, Rolf
    Göransson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Jonsson, Per R.
    Bohlin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Antifouling activity of a dibrominated cyclopeptide from the marine sponge Geodia barretti2008In: Journal of natural products (Print), ISSN 0163-3864, E-ISSN 1520-6025, Vol. 71, no 3, p. 330-333Article in journal (Refereed)
    Abstract [en]

    Many sessile suspension-feeding marine organisms rely on chemical defense to keep their surfaces free from fouling organisms. The brominated cyclopeptides barettin (cyclo[(6-bromo-8-entryptophan)arginine]) (1) and 8,9-dihydrobarettin (cyclo[(6-bromotryptophan)arginine]) (2) from the cold-water sponge Geodia barretti have previously displayed settlement inhibition of barnacle larvae in a dose-dependent manner. In this paper, we describe a novel dibrominated cyclopeptide, bromobenzisoxazolone barettin (cyclo[(6-bromo-8-(6-bromobenzioxazol-3(1H)-one)-8-hydroxy)tryptophan)]arginine) (3), which we have isolated from G. barretti and which displays settlement inhibition of barnacle larvae (Balanus improvisus) with an EC50 value of 15 nM. The chemical structure was determined using MS and 2D-NMR.

123 1 - 50 of 109
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