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  • 1.
    Aarnio, Mikko
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Hall, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Ängeby-Möller, Kristina
    Gordh, Torsten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Sörensen, Jens
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Evaluation of  PET tracers [11C]D-deprenyl, [11C]L-dideuteriumdeprenyl and [18F]FDG for Visualization of Acute Inflammation in a Rat Model of Pain - Preliminary Findings.Manuscript (preprint) (Other academic)
    Abstract [en]

    Purpose: Positron emission tomography with the radioligand [11C]D-deprenyl has shown an increased signal at the location of pain in patients with ankle sprains, rheumatoid arthritis and chronic whiplash injury, but the mechanism of this tracer uptake and its exact binding site in inflammation or tissue injury is still unclear. The aim of this study was to further evaluate [11C]D-deprenyl´s usefulness as a marker of acute inflammation.

    Methods: An animal PET/CT study was performed three days after the induction of a rat model of inflammatory or surgical pain. Fourteen adult male Sprague-Dawley rats and three tracers [11C]D-deprenyl, [11C]L-dideuterumdeprenyl and [18F]fluorodeoxyglucose were used.

    Results: No [11C]D-deprenyl accumulation was seen in a rat model of musculoskeletal pain. In the rat model of inflammatory pain all three ligands were shown to visualize the inflamed ankle joint with much lower uptake in the control ankle joint. The uptake was largest with [11C]D-deprenyl and [11C]L- dideuteriumdeprenyl, where approximately 1 % of the injected dose could be found in the affected ankle joint during the first minutes, whereas the uptake of [18F]FDG was approximately 0.5 % of the injected dose. However, the ratio of uptake of the injected ankle joint versus the control ankle joint was much higher for [18F]FDG (around 10 fold increase) than for the two deprenyl enantiomers (2 – 3 fold increase). The uptake pattern of [11C]D-deprenyl and [11C]L-dideuteriumdeprenyl did not show signs of specific binding or irreversible trapping.

    Conclusions: Contrary to our expectations, of the three tracers only [18F]FDG may be used as markers of peripheral inflammation in a rat model of inflammatory pain. However, as a high site-specificity is required, [11C]D-deprenyl and [11C]L-dideyteriumdeprenyl deserve further exploration regarding sensitivity, specificity and uptake mechanisms in human pain syndromes.

  • 2.
    Abd El-Gaber, Amira S.
    et al.
    Menoufia Univ, Fac Sci, Dept Chem, Shibin Al Kawm, Egypt.
    El Gendy, Abdel Nasser G.
    Natl Res Ctr, Med & Aromat Plants Res Dept, 33 El Bohouth St,PO 12622, Giza, Egypt.
    Elkhateeb, Ahmed
    Natl Res Ctr, Phytochem & Plant Systemat Dept, 33 El Bohouth St,PO 12622, Giza, Egypt.
    Saleh, Ibrahim A.
    Natl Res Ctr, Phytochem Dept, 33 El Bohouth St,PO 12622, Giza, Egypt.
    El-Seedi, Hesham
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Farmakognosi. Menoufia Univ, Fac Sci, Dept Chem, Shibin Al Kawm, Egypt;Univ Karachi, ICCBS, Karachi 75270, Pakistan.
    Microwave Extraction of Essential Oil from Anastatica hierochuntica (L): Comparison with Conventional Hydro-Distillation and Steam Distillation2018In: Journal of Essential Oil-Bearing Plants (JEOBP), ISSN 0972-060X, E-ISSN 0976-5026, Vol. 21, no 4, p. 1003-1010Article in journal (Refereed)
    Abstract [en]

    This article stands to introduce microwave assisted extraction (MAE) as a more effective method for extraction of Anastatica hierochuntica (L) essential oils (EOs) compared to traditional hydrodistillation (HD) and steam distillation (SD) methods. Analysis of EOs by gas chromatography-mass spectrometry (GC/MS) showed significant differences in the constituents and percentages of the obtained oils. Using MAE and HD obtained oxygenated monoterpenes 50.79 % whereas SD obtained sesquiterpene hydrocarbons 79.84 % as major contents of the extracted oils. This is the first report of EO composition of the aerials parts of A. heirochunatica. It offered several advantages of MAE technique as a green method with shorter extraction time (60 min) and better yield.

  • 3.
    Abdelmoniem, Amr M.
    et al.
    Cairo Univ, Dept Chem, Fac Sci, Giza, Egypt.
    Elnagdi, Mohamed H.
    Cairo Univ, Giza, Egypt;Kuwait Univ, Safat, Kuwait.
    Elsehemy, Mohamed S.
    Cairo Univ, Dept Chem, Fac Pharm, Giza, Egypt.
    El-Seedi, Hesham R.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Farmakognosi. Menoufia Univ, Dept Chem, Fac Sci, Shibin Al Kawm 32512, Egypt.
    Abdelhamid, Ismail A.
    Cairo Univ, Dept Chem, Fac Sci, Giza, Egypt.
    Synthesis, Chemistry and Utilities of Diaminoazoles with Special Reference to 3,5-Diaminopyrazoles2018In: Current Organic Synthesis, ISSN 1570-1794, E-ISSN 1875-6271, Vol. 15, no 4, p. 487-514Article, review/survey (Refereed)
    Abstract [en]

    Background: Although the chemistry of heteroaromatic monoamino azoles has been surveyed more than once in the last decade, the chemistry of the di- and triaminoazoles has not been reviewed. In this article we will survey the synthesis, chemistry and utility of the diaminoazoles. In this review, the chemistry of the diaminoazoles as well as their most important utilities will be surveyed. Objective: The review focuses on recent progress in diaminoazoles (i.e. diaminopyrazoles, diaminoimidazoles, diaminotriazoles and diaminothiazole) with especial references to diaminopyrazoles. The synthesis as well as pharmaceutical utilities are reported. There are several methods for synthesis of diaminopyrazoles. 3,5-Diaminopyrazole and its derivatives are prepared through the reaction of malononitrile or arylhydrazononitrile with hydrazine derivatives. 3,4-Diaminopyrazoles are prepared via nitration of 3-aminopyrazole with subsequent reduction of the produced compound. The diaminopyrazoles have several applications in cosmetic and pharmaceutical industries. They also have useful utilities as a constituent in oxidative hair dyes. Conclusion: We managed to report the common methods for the synthesis of diaminoazoles with especial reference to aminopyrazoles that are prepared through the reaction of malononitrile or hydrazononitriles with hydrazine derivatives. Some important applications that include pharmaceutical utilities such as hair dye constituents are reported.

  • 4.
    AbdelRehim, M
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Karlen, A
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Zhang, L
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Kamel, M
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Hassan, M
    Enantiomer separation of underivatized tocainide and related compounds by CGC using ammonia as carrier gas1996In: JOURNAL OF MICROCOLUMN SEPARATIONS, Vol. 8, p. 151-Article in journal (Refereed)
  • 5.
    Abdel-Rehim, Mohamed
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Hassan, Moustapha
    Capillary gas chromatography of trichlorophenols using ammonia as carrier gas2000In: Journal of High Resolution Chromatography, Vol. 23, p. 156-Article in journal (Refereed)
  • 6.
    Abdillahi, Suado M.
    et al.
    Lund Univ, Div Infect Med, Dept Clin Sci, Tornavagen 10, S-22184 Lund, Sweden.
    Maass, Tobias
    Univ Cologne, Fac Med, Ctr Biochem, Ctr Mol Med Cologne, D-50931 Cologne, Germany.
    Kasetty, Gopinath
    Lund Univ, Div Resp Med & Allergol, Dept Clin Sci, S-22184 Lund, Sweden.
    Strömstedt, Adam A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Farmakognosi.
    Baumgarten, Maria
    Lund Univ, Div Infect Med, Dept Clin Sci, Tornavagen 10, S-22184 Lund, Sweden.
    Tati, Ramesh
    Lund Univ, Div Infect Med, Dept Clin Sci, Tornavagen 10, S-22184 Lund, Sweden.
    Nordin, Sara L.
    Lund Univ, Div Infect Med, Dept Clin Sci, Tornavagen 10, S-22184 Lund, Sweden.
    Walse, Björn
    Sarom Biostruct AB, S-22363 Lund, Sweden.
    Wagener, Raimund
    Univ Cologne, Fac Med, Ctr Biochem, Ctr Mol Med Cologne, D-50931 Cologne, Germany.
    Schmidtchen, Artur
    Lund Univ, Div Dermatol & Venereol, Dept Clin Sci, S-22184 Lund, Sweden;Univ Copenhagen, Bispebjerg Hosp, Dept Biomed Sci, Copenhagen Wound Healing Ctr, DK-2400 Copenhagen, Denmark.
    Mörgelin, Matthias
    Lund Univ, Div Infect Med, Dept Clin Sci, Tornavagen 10, S-22184 Lund, Sweden;Colzyx AB, S-22381 Lund, Sweden.
    Collagen VI Contains Multiple Host Defense Peptides with Potent In Vivo Activity2018In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 201, no 3, p. 1007-1020Article in journal (Refereed)
    Abstract [en]

    Collagen VI is a ubiquitous extracellular matrix component that forms extensive microfibrillar networks in most connective tissues. In this study, we describe for the first time, to our knowledge, that the collagen VI von Willebrand factor type A like domains exhibit a broad-spectrum antimicrobial activity against Gram-positive and Gram-negative bacteria in human skin infections in vivo. In silico sequence and structural analysis of VWA domains revealed that they contain cationic and amphipathic peptide sequence motifs, which might explain the antimicrobial nature of collagen VI. In vitro and in vivo studies show that these peptides exhibited significant antibacterial activity against Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa through membrane disruption. Our findings shed new light on the role of collagen VI derived peptides in innate host defense and provide templates for development of peptide-based antibacterial therapies.

  • 7.
    Abouzayed, Ayman
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics.
    Yim, Cheng-Bin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics.
    Mitran, Bogdan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics.
    Rinne, Sara S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics.
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Larhed, Mats
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics.
    Rosenström, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Synthesis and Preclinical Evaluation of Radio-Iodinated GRPR/PSMA Bispecific Heterodimers for the Theranostics Application in Prostate Cancer2019In: Pharmaceutics, ISSN 1999-4923, E-ISSN 1999-4923, Vol. 11, no 7, article id 358Article in journal (Refereed)
    Abstract [en]

    Gastrin-releasing peptide receptor (GRPR) and prostate-specific membrane antigen (PSMA) are overexpressed in most prostate cancers. GRPR expression is higher in early stages while PSMA expression increases with progression. The possibility of targeting both markers with a single theranostics radiotracer could improve patient management. Three GRPR/PSMA-targeting bispecific heterodimers (urea derivative PSMA-617 and bombesin-based antagonist RM26 linked via X-triazolyl-Tyr-PEG2, X = PEG2 (BO530), (CH2)(8) (BO535), none (BO536)) were synthesized by solid-phase peptide synthesis. Peptides were radio-iodinated and evaluated in vitro for binding specificity, cellular retention, and affinity. In vivo specificity for all heterodimers was studied in PC-3 (GRPR-positive) and LNCaP (PSMA-positive) xenografts. [I-125]I-BO530 was evaluated in PC-3pip (GRPR/PSMA-positive) xenografts. Micro single-photon emission computed tomography/computed tomography (microSPECT/CT) scans were acquired. The heterodimers were radiolabeled with high radiochemical yields, bound specifically to both targets, and demonstrated high degree of activity retention in PC-3pip cells. Only [I-125]I-BO530 demonstrated in vivo specificity to both targets. A biodistribution study of [I-125]I-BO530 in PC-3pip xenografted mice showed high tumor activity uptake (30%-35%ID/g at 3 h post injection (pi)). Activity uptake in tumors was stable and exceeded all other organs 24 h pi. Activity uptake decreased only two-fold 72 h pi. The GRPR/PSMA-targeting heterodimer [I-125]I-BO530 is a promising agent for theranostics application in prostate cancer.

  • 8.
    Aboye, Teshome L.
    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.
    Göransson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Synthesis, Cyclization and Oxidative folding of backbone engineered Cyclotides2010Conference paper (Refereed)
  • 9.
    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.

  • 10.
    Aboye, Teshome Leta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Engineering of the Ultra-stable Cystine Knot Framework of Microproteins: Design, Chemical Synthesis and Structural Studies2011Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Ultra-stable cystine knotted microproteins, in which two disulfides and their connecting backbones form a circle that is penetrated by the third disulfide bonds, have attracted high interest due to their resistance to degradation in vitro and potential for the development of peptide drugs. This thesis gives new insights into engineering of that framework of microproteins, including approaches to their chemical synthesis, backbone engineering, structural and biological evaluations.

    Synthetic and oxidative folding approaches for bracelet cyclotides, a family of cyclic cystine knotted microproteins, was developed using a model peptide, cycloviolacin O2. Following assembly of the peptide chain, protected peptide was generated by mild cleavage that was subsequently thioesterified and cyclized in solution. The cyclic peptide was oxidatively folded under optimized conditions containing co-solvent and non-ionic detergent affording native cycloviolacin O2 as a major product. To gain further insights into the heterogeneity, efficiency and kinetics of cyclotides’ oxidative folding, the intermediates that accumulate in oxidative refolding pathways of all cyclotide subfamilies: Möbius, bracelet and the hybrid cyclotides were quantitatively determined under four different folding conditions. The results were used for defining major folding pathways, which indicated that Möbius cyclotides might accumulate heterogeneous folding intermediates with one-, two- and three-disulfides, whereas bracelet tend to accumulate a homogenous intermediate with three-disulfides, depending on the buffer systems used.

    Furthermore, to probe the internal factors contributing to inefficiency of oxidative folding, as well as undesired bioactivities of bracelet cyclotides (e.g., cytotoxic activity), polymer-hybridized cyclotides were designed by replacing non-conserved residues with small isosteric polymers. The designed hybrid analogs in which hybridization involved replacement of loop 3 with isosteric polymers showed improved synthetic and oxidative folding properties. The cytoxicity of a model hybrid designed with replacement of loop 3 and 5 exhibited no cytotoxic activity at concentration of 128-fold relative to that of native peptide. Furthermore, 1D and 2D 1H NMR analysis of this hybrid showed that it had well structured fold.

    List of papers
    1. Discovery, synthesis, and structural determination of a toxine-like disulfide-rich peptide from the cactus Trichoserus pachanoi
    Open this publication in new window or tab >>Discovery, synthesis, and structural determination of a toxine-like disulfide-rich peptide from the cactus Trichoserus pachanoi
    Show others...
    (English)Manuscript (preprint) (Other academic)
    Identifiers
    urn:nbn:se:uu:diva-145716 (URN)
    Available from: 2011-02-10 Created: 2011-02-10 Last updated: 2011-05-04
    2. Ultra-stable peptide scaffolds for protein engineering-synthesis and folding of the circular cystine knotted cyclotide cycloviolacin O2
    Open this publication in new window or tab >>Ultra-stable peptide scaffolds for protein engineering-synthesis and folding of the circular cystine knotted cyclotide cycloviolacin O2
    2008 (English)In: ChemBioChem (Print), ISSN 1439-4227, E-ISSN 1439-7633, Vol. 9, no 1, p. 103-113Article in journal (Refereed) Published
    Abstract [en]

    The cyclic cystine knot motif, as defined by the cyclotide peptide family, is an attractive scaffold for protein engineering. To date, however, the utilisation of this scaffold has been limited by the inability to synthesise members of the most diverse and biologically active subfamily, the bracelet cyclotides. This study describes the synthesis and first direct oxidative folding of a bracelet cyclotide-cycloviolacin O2-and thus provides an efficient method for exploring the most potent cyclic cystine knot peptides. The linear chain of cycloviolacin O2 was assembled by solid-phase Fmoc peptide synthesis and cyclised by thioester-mediated native chemical ligation, and the inherent difficulties of folding bracelet cyclotides were successfully overcome in a single-step reaction. The folding pathway was characterised and was found to include predominating fully oxidised intermediates that slowly converted to the native peptide structure.

    Keywords
    cyclotides, native chemical ligation, peptides, protein folding, synthesis, thioesters
    National Category
    Pharmaceutical Sciences
    Identifiers
    urn:nbn:se:uu:diva-98767 (URN)10.1002/cbic.200700357 (DOI)000252292200017 ()18058973 (PubMedID)
    Available from: 2009-03-03 Created: 2009-03-03 Last updated: 2018-01-13Bibliographically approved
    3. An Efficient Approach for the Total Synthesis of Cyclotides by Microwave Assisted Fmoc-SPPS
    Open this publication in new window or tab >>An Efficient Approach for the Total Synthesis of Cyclotides by Microwave Assisted Fmoc-SPPS
    2010 (English)In: International Journal of Peptide Research and Therapeutics, ISSN 1573-3149, Vol. 16, no 3, p. 167-176Article in journal (Refereed) Published
    Abstract [en]

    Cyclotides are mini-proteins of approximately 30 amino acid residues that have a unique structure consisting of a head-to-tail cyclized backbone and a knotted arrangement of three disulfide bonds. This unique cyclotide structure provides exceptional stability to chemical, enzymatic and thermal treatments and has been implicated as an ideal drug scaffold for the development into agricultural and biotechnological agents. In the current work, we present the first method for microwave assisted Fmoc-SPPS of cyclotides. This protocol adopts a strategy that combines optimized microwave assisted chemical reactions for Fmoc-SPPS of the peptide backbone, the cleavage of the protected peptide and the introduction of a thioester at the C-terminal carboxylic acid to obtain the head-to-tail cyclized cyclotide backbone by native chemical ligation. To exemplify the utility of this protocol in the synthesis of a wide array of different cyclotide sequences we synthesized representative members from the three cyclotide subfamilies-the Mobius kalata B1, the bracelet cycloviolacin O2 and the trypsin inhibitory MCoTI-II. In addition, a "one pot" reaction promoting both cyclization and oxidative folding of crude peptide thioester was adapted for kalata B1 and MCoTI-II.

    Keywords
    Cyclotides, Microwave chemistry, Fmoc-SPPS, Circular proteins, Cystine knot, Native chemical ligation
    National Category
    Pharmaceutical Sciences
    Identifiers
    urn:nbn:se:uu:diva-134899 (URN)10.1007/s10989-010-9221-0 (DOI)000281682600007 ()
    Available from: 2010-12-02 Created: 2010-12-02 Last updated: 2018-01-12Bibliographically approved
    4. Interlocking disulfides in circular proteins: toward efficient oxidative folding of cyclotides.
    Open this publication in new window or tab >>Interlocking disulfides in circular proteins: toward efficient oxidative folding of cyclotides.
    Show others...
    2011 (English)In: Antioxidants and Redox Signaling, ISSN 1523-0864, E-ISSN 1557-7716, Vol. 14, no 1, p. 77-86Article in journal (Refereed) Published
    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.

    National Category
    Pharmaceutical Sciences
    Identifiers
    urn:nbn:se:uu:diva-139359 (URN)10.1089/ars.2010.3112 (DOI)000284572100009 ()20486762 (PubMedID)
    Available from: 2010-12-23 Created: 2010-12-23 Last updated: 2018-01-12Bibliographically approved
    5. Design, synthesis, structural and biological evaluation of backbone-engineered cyclotides
    Open this publication in new window or tab >>Design, synthesis, structural and biological evaluation of backbone-engineered cyclotides
    (English)Manuscript (preprint) (Other academic)
    Identifiers
    urn:nbn:se:uu:diva-145719 (URN)
    Available from: 2011-02-10 Created: 2011-02-10 Last updated: 2011-05-04
  • 11.
    Aboye, Teshome Leta
    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.
    Göransson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Design, synthesis, structural and biological evaluation of backbone-engineered cyclotidesManuscript (preprint) (Other academic)
  • 12.
    Aboye, Teshome Leta
    et al.
    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.
    Burman, Robert
    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, Division of Pharmacognosy.
    Synthesis and Oxidative Folding of Cyclic Cystine Knot Peptides: Towards Backbone Engineering2010In: Peptides 2010: Tales of Peptides Proceedings of the Thirty-First European Peptide Symposium / [ed] Michal Lebl, Morten Meldal, Knud J. Jensen, Thomas Høeg-Jensen, European Peptide Society , 2010, p. 142-143Conference paper (Refereed)
  • 13.
    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.

  • 14.
    Aboye, Teshome Leta
    et al.
    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 Pharmacy, Department of Medicinal Chemistry.
    Clark, Richard. J.
    University of Queensland, Institute for Molecular Bioscience.
    Craik, David J.
    University of Queensland, Institute for Molecular Bioscience.
    Goransson, Ulf
    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 Pharmacy, Department of Medicinal Chemistry.
    Synthesis and folding of the circular cystine knotted cyclotide cycloviolacin O2.2008In: Planta Medica, ISSN 0032-0943, E-ISSN 1439-0221, Vol. 74, no 9, p. 1158-1158Article in journal (Refereed)
  • 15.
    Aboye, Teshome Leta
    et al.
    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.
    Göransson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Synthesis and folding of the circular cystine knotted cyclotide cycloviolacin O22008In: Peptides 2008: Chemistry of Peptides in Life Science Technology and MedicineProceedings of The Thirtieth European Peptide Symposium / [ed] Hilkka Lankinen, The Finnish Peptide Society and The European Peptide Society , 2008, p. 280-281Conference paper (Refereed)
  • 16.
    Aboye, Teshome Leta
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Rosengren, Johan
    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, G. Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    El-Seedi, Hesham
    Göransson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Discovery, synthesis, and structural determination of a toxine-like disulfide-rich peptide from the cactus Trichoserus pachanoiManuscript (preprint) (Other academic)
  • 17.
    Acuna, UM
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Atha, DE
    Ma, J
    Nee, MH
    Kennelly, EJ
    Antioxidant capacities of ten edible North American plants.2002In: Phytother Res, Vol. 16, p. 63-Article in journal (Refereed)
  • 18.
    Adeyemi, Ahmed
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Bergman, Joakim
    AstraZeneca, Dept Med Chem Cardiovasc & Metab Dis, Innovat Med & Early Dev Biotech Unit, Pepparedsleden 1, S-43183 Molndal, Sweden..
    Branalt, Jonas
    AstraZeneca, Dept Med Chem Cardiovasc & Metab Dis, Innovat Med & Early Dev Biotech Unit, Pepparedsleden 1, S-43183 Molndal, Sweden..
    Sävmarker, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Larhed, Mats
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Continuous Flow Synthesis under High-Temperature/High-Pressure Conditions Using a Resistively Heated Flow Reactor2017In: Organic Process Research & Development, ISSN 1083-6160, E-ISSN 1520-586X, Vol. 21, no 7, p. 947-955Article in journal (Refereed)
    Abstract [en]

    A cheap, easy-to-build, and effective resistively heated reactor for continuous flow synthesis at high temperature and pressure is herein presented. The reactor is rapidly heated directly using, an electric current and is capable of rapidly delivering temperatures and pressures up to 400 degrees C and 200 bar, respectively. High-temperature and high-pressure applications of this reactor were safely performed and demonstrated by selected transformations such as esterifications, transesterifications, and direct carboxylic acid to nitrile reactions using supercritical ethanol, methanol, and acetonitrile. Reaction temperatures were between 300 and 400 degrees C with excellent conversions and good to excellent isolated product yields. Examples of Diels-Alder reactions were also carried out at temperatures up to 300 degrees C in high yield. No additives or catalysts were used in the reactions.

  • 19.
    Adeyemi, Ahmed
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Wetzel, Alexander
    AstraZeneca, Dept Med Chem, Cardiovasc Renal & Metab IMED Biotech Unit, Pepparedsleden 1, S-43183 Molndal, Sweden.
    Bergman, Joakim
    AstraZeneca, Dept Med Chem, Cardiovasc Renal & Metab IMED Biotech Unit, Pepparedsleden 1, S-43183 Molndal, Sweden.
    Brånalt, Jonas
    AstraZeneca, Dept Med Chem, Cardiovasc Renal & Metab IMED Biotech Unit, Pepparedsleden 1, S-43183 Molndal, Sweden.
    Larhed, Mats
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Regio- and Stereoselective Synthesis of Spirooxindoles via Mizoroki-Heck Coupling of Aryl Iodides2019In: Synlett: Accounts and Rapid Communications in Synthetic Organic Chemistry, ISSN 0936-5214, E-ISSN 1437-2096, Vol. 30, no 1, p. 82-88Article in journal (Refereed)
    Abstract [en]

    A method for highly regio- and stereoselective intramolecular Mizoroki-Heck 5- exo cyclization of aryl iodides to the corresponding spirooxindoles has been developed. Electron-rich and electron-deficient aryl iodide precursors were selectively ring-closed with high stereoselectivity and good yields. The double-bond position in the cyclopentene ring was controlled by careful choice of reaction conditions. These rare spiro compounds were further functionalized to rigidified unnatural amino acid derivatives by a subsequent gas-free Pd(0)-catalyzed alkoxycarbonylation, followed by selective O - and N -deprotections.

  • 20.
    Adl, Sina M.
    et al.
    Univ Saskatchewan, Dept Soil Sci, Coll Agr & Bioresources, 51 Campus Dr, Saskatoon, SK S7N 5A8, Canada.
    Bass, David
    Nat Hist Museum, Dept Life Sci, Cromwell Rd, London SW7 5BD, England;CEFAS, Barrack Rd, Weymouth DT4 8UB, Dorset, England.
    Lane, Christopher E.
    Univ Rhode Isl, Dept Biol Sci, Kingston, RI 02881 USA.
    Lukes, Julius
    Czech Acad Sci, Biol Ctr, Inst Parasitol, Ceske Budejovice 37005, Czech Republic;Univ South Bohemia, Fac Sci, Ceske Budejovice 37005, Czech Republic.
    Schoch, Conrad L.
    Natl Inst Biotechnol Informat, Natl Lib Med, NIH, Bethesda, MD 20892 USA.
    Smirnov, Alexey
    St Petersburg State Univ, Fac Biol, Dept Invertebrate Zool, St Petersburg 199034, Russia.
    Agatha, Sabine
    Univ Salzburg, Dept Biosci, Hellbrunnerstr 34, A-5020 Salzburg, Austria.
    Berney, Cedric
    CNRS, UMR 7144 AD2M, Grp Evolut Protistes & Ecosyst Pelag, Stn Biol Roscoff, Pl Georges Teissier, F-29680 Roscoff, France.
    Brown, Matthew W.
    Mississippi State Univ, Dept Biol Sci, Starkville, MS 39762 USA;Mississippi State Univ, Inst Genom Biocomp & Biotechnol, Starkville, MS 39762 USA.
    Burki, Fabien
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Systematic Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Cárdenas, Paco
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Farmakognosi.
    Cepicka, Ivan
    Charles Univ Prague, Dept Zool, Fac Sci, Vinicna 7, CR-12844 Prague, Czech Republic.
    Chistyakova, Lyudmila
    St Petersburg State Univ, Core Facil Ctr Culture Collect Microorganisms, St Petersburg 198504, Russia.
    del Campo, Javier
    CSIC, Inst Ciencies Mar, Passeig Maritim Barceloneta 37-49, E-08003 Barcelona, Catalonia, Spain.
    Dunthorn, Micah
    Univ Kaiserslautern, Dept Ecol, Erwin Schroedinger St, D-67663 Kaiserslautern, Germany;Univ Duisburg Essen, Dept Eukaryot Microbiol, Univ Str 5, D-45141 Essen, Germany.
    Edvardsen, Bente
    Univ Oslo, Dept Biosci, POB 1066 Blindern, N-0316 Oslo, Norway.
    Eglit, Yana
    Dalhousie Univ, Dept Biol, Halifax B3H 4R2, NS, Canada.
    Guillou, Laure
    Univ Paris 06, Sorbonne Univ, Paris 6, CNRS,UMR 7144 AD2M,Stn Biol Roscoff, Pl Georges Teissier,,CS90074, F-29688 Roscoff, France.
    Hampl, Vladimir
    Charles Univ Prague, Dept Parasitol, Fac Sci, BIOCEV, Prumyslov 595, Vestec 25242, Czech Republic.
    Heiss, Aaron A.
    Amer Museum Nat Hist, Dept Invertebrate Zool, New York, NY 10024 USA.
    Hoppenrath, Mona
    DZMB German Ctr Marine Biodivers Res, D-26382 Wilhelmshaven, Germany.
    James, Timothy Y.
    Univ Michigan, Dept Ecol & Evolutionary Biol, Ann Arbor, MI 48109 USA.
    Karnkowska, Anna
    Univ Warsaw, Dept Mol Phylogenet & Evolut, PL-02089 Warsaw, Poland.
    Karpov, Sergey
    St Petersburg State Univ, Fac Biol, Dept Invertebrate Zool, St Petersburg 199034, Russia;RAS, Lab Parasit Worms & Protistol, Zool Inst, St Petersburg 199034, Russia.
    Kim, Eunsoo
    Amer Museum Nat Hist, Dept Invertebrate Zool, New York, NY 10024 USA.
    Kolisko, Martin
    Czech Acad Sci, Biol Ctr, Inst Parasitol, Ceske Budejovice 37005, Czech Republic.
    Kudryavtsev, Alexander
    St Petersburg State Univ, Fac Biol, Dept Invertebrate Zool, St Petersburg 199034, Russia;RAS, Lab Parasit Worms & Protistol, Zool Inst, St Petersburg 199034, Russia.
    Lahr, Daniel J. G.
    Univ Sao Paulo, Dept Zool, Inst Biosci, Matao Travessa 14 Cidade Univ, BR-05508090 Sao Paulo, SP, Brazil.
    Lara, Enrique
    Univ Neuchatel, Lab Soil Biodivers, Rue Emile Argand 11, CH-2000 Neuchatel, Switzerland;CSIC, Real Jardim Bot,Plaza Murillo 2, E-28014 Madrid, Spain.
    Le Gall, Line
    Sorbonne Univ, Museum Natl Hist Nat, Inst Systemat Evolut Biodiversit, 57 Rue Cuvier,CP 39, F-75005 Paris, France.
    Lynn, Denis H.
    Univ Guelph, Dept Integrat Biol, Summerlee Sci Complex, Guelph, ON N1G 2W1, Canada;Univ British Columbia, Dept Zool, 4200-6270 Univ Blvd, Vancouver, BC V6T 1Z4, Canada.
    Mann, David G.
    Royal Bot Garden, Edinburgh EH3 5LR, Midlothian, Scotland;Inst Agrifood Res & Technol, C Poble Nou Km 5-5, E-43540 San Carlos de la Rapita, Spain.
    Massana, Ramon
    CSIC, Inst Ciencies Mar, Passeig Maritim Barceloneta 37-49, E-08003 Barcelona, Catalonia, Spain.
    Mitchell, Edward A. D.
    Univ Neuchatel, Lab Soil Biodivers, Rue Emile Argand 11, CH-2000 Neuchatel, Switzerland;Jardin Bot Neuchatel,Chemin Perthuis du Salut 58, CH-2000 Neuchatel, Switzerland.
    Morrow, Christine
    Natl Museums Northern Ireland, Dept Nat Sci, 153 Bangor Rd, Holywood BT18 0EU, England.
    Park, Jong Soo
    Kyungpook Natl Univ, Sch Earth Syst Sci, Dept Oceanog, Daegu, South Korea;Kyungpook Natl Univ, Sch Earth Syst Sci, Kyungpook Inst Oceanog, Daegu, South Korea.
    Pawlowski, Jan W.
    Univ Geneva, Dept Genet & Evolut, CH-1211 Geneva 4, Switzerland.
    Powell, Martha J.
    Univ Alabama, Dept Biol Sci, Tuscaloosa, AL 35487 USA.
    Richter, Daniel J.
    Univ Pompeu Fabra, CSIC, Inst Biol Evolut, Passeig Maritim Barceloneta 37-49, Barcelona 08003, Spain.
    Rueckert, Sonja
    Edinburgh Napier Univ, Sch Appl Sci, Edinburgh EH11 4BN, Midlothian, Scotland.
    Shadwick, Lora
    Univ Arkansas, Dept Biol Sci, Fayetteville, AR 72701 USA.
    Shimano, Satoshi
    Hosei Univ, Sci Res Ctr, Chiyoda Ku, 2-17-1 Fujimi, Tokyo, Japan.
    Spiegel, Frederick W.
    Univ Arkansas, Dept Biol Sci, Fayetteville, AR 72701 USA.
    Torruella, Guifre
    Univ Paris XI, Lab Evolut & Systemat, F-91405 Orsay, France.
    Youssef, Noha
    Oklahoma State Univ, Dept Microbiol & Mol Genet, Stillwater, OK 74074 USA.
    Zlatogursky, Vasily V.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Systematic Biology. St Petersburg State Univ, Fac Biol, Dept Invertebrate Zool, St Petersburg 199034, Russia.
    Zhang, Qianqian
    Chinese Acad Sci, Yantai Inst Coastal Zone Res, Yantai 264003, Peoples R China.
    Revisions to the Classification, Nomenclature, and Diversity of Eukaryotes2019In: Journal of Eukaryotic Microbiology, ISSN 1066-5234, E-ISSN 1550-7408, Vol. 66, no 1, p. 4-119Article in journal (Refereed)
    Abstract [en]

    This revision of the classification of eukaryotes follows that of Adl et al., 2012 [J. Euk. Microbiol. 59(5)] and retains an emphasis on protists. Changes since have improved the resolution of many nodes in phylogenetic analyses. For some clades even families are being clearly resolved. As we had predicted, environmental sampling in the intervening years has massively increased the genetic information at hand. Consequently, we have discovered novel clades, exciting new genera and uncovered a massive species level diversity beyond the morphological species descriptions. Several clades known from environmental samples only have now found their home. Sampling soils, deeper marine waters and the deep sea will continue to fill us with surprises. The main changes in this revision are the confirmation that eukaryotes form at least two domains, the loss of monophyly in the Excavata, robust support for the Haptista and Cryptista. We provide suggested primer sets for DNA sequences from environmental samples that are effective for each clade. We have provided a guide to trophic functional guilds in an appendix, to facilitate the interpretation of environmental samples, and a standardized taxonomic guide for East Asian users.

  • 21.
    Aftab, Obaid
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Engskog, Mikael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Haglöf, Jakob
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Elmsjö, Albert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Arvidsson, Torbjörn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Pettersson, Curt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Hammerling, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Gustafsson, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    NMR spectroscopy based metabolic profiling of drug induced changes in vitro can discriminate between pharmacological classes2014In: Journal of chemical information and modeling, ISSN 1549-9596, Vol. 54, no 11, p. 3251-3258Article in journal (Refereed)
    Abstract [en]

    Drug induced changes in mammalian cell line models have already been extensively profiled at the systemic mRNA level and subsequently used to suggest mechanisms of action for new substances as well as to support drug repurposing, i.e. identifying new potential indications for drugs already licensed for other pharmacotherapy settings. The seminal work in this field, which includes a large database and computational algorithms for pattern matching, is known as the “Connectivity Map” (CMap). The potential of similar exercises at the metabolite level is, however, still largely unexplored. Only recently the first high throughput metabolomic assay pilot study was published, involving screening of metabolic response to a set of 56 kinase inhibitors in a 96-well format. Here we report results from a separately developed metabolic profiling assay, which leverages 1H NMR spectroscopy to the quantification of metabolic changes in the HCT116 colorectal cancer cell line, in response to each of 26 compounds. These agents are distributed across 12 different pharmacological classes covering a broad spectrum of bioactivity. Differential metabolic profiles, inferred from multivariate spectral analysis of 18 spectral bins, allowed clustering of most tested drugs according to their respective pharmacological class. A more advanced supervised analysis, involving one multivariate scattering matrix per pharmacological class and using only 3 spectral bins (three metabolites), showed even more distinct pharmacology-related cluster formations. In conclusion, this kind of relatively fast and inexpensive profiling seems to provide a promising alternative to that afforded by mRNA expression analysis, which is relatively slow and costly. As also indicated by the present pilot study, the resulting metabolic profiles do not seem to provide as information rich signatures as those obtained using systemic mRNA profiling, but the methodology holds strong promise for significant refinement.

  • 22.
    Afzelius, L
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Masimirembwa, CM
    Karlen, A
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Andersson, TB
    Zamora, I
    Discriminant and quantitative PLS analysis of competitive CYP2C9 inhibitors versus non-inhibitors using alignment independent GRIND descriptors2002In: JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN, Vol. 16, p. 443-Article in journal (Refereed)
  • 23. Afzelius, L
    et al.
    Zamora, I
    Ridderstrom, M
    Andersson, TB
    Karlen, A
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Masimirembwa, CM
    Competitive CYP2C9 inhibitors: enzyme inhibition studies, protein homologymodeling, and three-dimensional quantitative structure-activityrelationship analysis.2001In: Mol Pharmacol, Vol. 59, p. 909-Article in journal (Refereed)
  • 24.
    Afzelius, Lovisa
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Computational Modelling of Structures and Ligands of CYP2C92004Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    CYP2C9 is one of our major drug metabolising enzymes and belongs to the cytochrome P450 (CYP) super family. The aim of this thesis was to gain an understanding of the quantitative structure–activity relationships (QSAR) of CYP2C9 substrates and inhibitors. This information will be useful in predicting drug metabolism and the potential for drug–drug interactions. To achieve this, a well characterised data set of structurally diverse, competitive CYP2C9 inhibitors was identified in our laboratory. Several computational methodologies, many based on GRID molecular interaction fields, were applied or developed in order to handle issues such as compound alignment and bioactive conformer selection. First, a traditional 3D QSAR was carried out in GOLPE, generating a predictive model. In this model the selection of a bioactive conformer and alignment was based on docking in a homology model of CYP2C9. Secondly, we introduced the concept of alignment independent descriptors from ALMOND. These descriptors were used to generate quantitatively and qualitatively predictive models. We subsequently derived conformation independent descriptors from molecular interaction fields calculated in FlexGRID. This enabled the derivation of 3D QSAR models without taking into account the selection of an alignment or a bioactive conformer. A subsequent programming effort enabled the conversion of this model back to 3D aligned pharmacophores. Similar alignment independent descriptors were also used in the development of the software MetaSite® that predicts the site of metabolism for CYP2C9 ligands. Finally, as crystal information on this isoform emerged, the performance of molecular dynamics simulations and homology models and the flexibility of the protein were evaluated using statistical analyses.

    These modelling efforts have resulted in detailed knowledge of the structural characteristics in ligand interactions with the cytochrome P450 2C9 isoform.

    List of papers
    1. Competitive CYP2C9 Inhibitors: Enzyme inhibition Studies, Protein Homology Modelling, and Three-Dimensional Quantitative Structure Activity Relationship Analysis
    Open this publication in new window or tab >>Competitive CYP2C9 Inhibitors: Enzyme inhibition Studies, Protein Homology Modelling, and Three-Dimensional Quantitative Structure Activity Relationship Analysis
    Show others...
    2001 In: Molecular Pharmacology, ISSN 0026-895, Vol. 59, p. 909 - 919Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-91425 (URN)
    Available from: 2004-02-27 Created: 2004-02-27Bibliographically approved
    2. Discriminant and quantitative PLS analysis of competitive CYP2C9 inhibitors versus non-inhibitors using alignment independent GRIND descriptors.
    Open this publication in new window or tab >>Discriminant and quantitative PLS analysis of competitive CYP2C9 inhibitors versus non-inhibitors using alignment independent GRIND descriptors.
    Show others...
    2002 In: Journal of Computer-Aided Molecular Design, ISSN 0920-654, Vol. 16, p. 443 - 458Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-91426 (URN)
    Available from: 2004-02-27 Created: 2004-02-27Bibliographically approved
    3. Predicting Drug Metabolism: A Site of Metabolism Tool Applied to the Cytochrome P450 CYP2C9.
    Open this publication in new window or tab >>Predicting Drug Metabolism: A Site of Metabolism Tool Applied to the Cytochrome P450 CYP2C9.
    2003 In: Journal of Medicinal Chemistry, ISSN 0022-2623, Vol. 46, no 12, p. 2313-2324Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-91427 (URN)
    Available from: 2004-02-27 Created: 2004-02-27Bibliographically approved
    4. A Conformer and Alignment independent model to predict structurally diverse competitive CYP2C9 inhibitors.
    Open this publication in new window or tab >>A Conformer and Alignment independent model to predict structurally diverse competitive CYP2C9 inhibitors.
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    2004 In: Journal of Medicinal Chemistry, ISSN 0022-2623, Vol. Web Release Date: 13-JanArticle in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-91428 (URN)
    Available from: 2004-02-27 Created: 2004-02-27Bibliographically approved
    5. Structural analysis of CYP2C9 and CYP2C5 and critical assessment of molecular modelling techniques.
    Open this publication in new window or tab >>Structural analysis of CYP2C9 and CYP2C5 and critical assessment of molecular modelling techniques.
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    Manuscript (Other academic)
    Identifiers
    urn:nbn:se:uu:diva-91429 (URN)
    Available from: 2004-02-27 Created: 2004-02-27 Last updated: 2010-01-13Bibliographically approved
    6. Virtual receptor site (VRS) derivation for competitive CYP2C9 inhibitors: - a novel approach for structurally diverse compounds.
    Open this publication in new window or tab >>Virtual receptor site (VRS) derivation for competitive CYP2C9 inhibitors: - a novel approach for structurally diverse compounds.
    Show others...
    Manuscript (Other academic)
    Identifiers
    urn:nbn:se:uu:diva-91430 (URN)
    Available from: 2004-02-27 Created: 2004-02-27 Last updated: 2010-01-13Bibliographically approved
  • 25.
    Afzelius, Lovisa
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Fontaine, Fabien
    Karlén, Anders
    Andersson, Tommy B.
    Masimirembwa, Collen
    Pastor, Manuel
    Zamora, Ismael
    Virtual receptor site (VRS) derivation for competitive CYP2C9 inhibitors: - a novel approach for structurally diverse compounds.Manuscript (Other academic)
  • 26.
    Afzelius, Lovisa
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Masimirembwa, Collen
    Karlén, Anders
    Andersson, Tommy B.
    Zamora, Ismael
    Discriminant and quantitative PLS analysis of competitive CYP2C9 inhibitors versus non-inhibitors using alignment independent GRIND descriptors.2002In: Journal of Computer-Aided Molecular Design, ISSN 0920-654, Vol. 16, p. 443 - 458Article in journal (Refereed)
  • 27.
    Afzelius, Lovisa
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry. Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry. OrgFarmKemi.
    Raubacher, Florian
    Karlen, Anders
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry. Department of Pharmacy. OrgFarmKemi.
    Jørgensen, Flemming Steen
    Andersson, Tommy B
    Masimirembwa, Collen M
    Zamora, Ismael
    Structural analysis of CYP2C9 and CYP2C5 and an evaluation of commonly used molecular modeling techniques.2004In: Drug Metab Dispos, ISSN 0090-9556, Vol. 32, no 11, p. 1218-29Article in journal (Refereed)
  • 28.
    Afzelius, Lovisa
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Raubacher, Florian
    Karlén, Anders
    Jørgensen, Flemming S.
    Andersson, Tommy B.
    Masimirembwa, Collen
    Zamora, Ismael
    Structural analysis of CYP2C9 and CYP2C5 and critical assessment of molecular modelling techniques.Manuscript (Other academic)
  • 29.
    Afzelius, Lovisa
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Zamora, Ismael
    Masimirembwa, Collen
    Karlén, Anders
    Andersson, Tommy B.
    Mecucci, Silvio
    Baroni, Massimo
    Cruciani, Gabriele
    A Conformer and Alignment independent model to predict structurally diverse competitive CYP2C9 inhibitors.2004In: Journal of Medicinal Chemistry, ISSN 0022-2623, Vol. Web Release Date: 13-JanArticle in journal (Refereed)
  • 30.
    Afzelius, Lovisa
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry. Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry. OrgFarmKemi.
    Zamora, Ismael
    Masimirembwa, Collen M
    Karlen, Anders
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry. Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Andersson, Tommy B
    Mecucci, Silvio
    Baroni, Massimo
    Cruciani, Gabriele
    Conformer- and alignment-independent model for predicting structurally diverse competitive CYP2C9 inhibitors.2004In: J Med Chem, ISSN 0022-2623, Vol. 47, no 4, p. 907-14Article in journal (Refereed)
  • 31.
    Afzelius, Lovisa
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Zamora, Ismael
    Ridderström, Marianne
    Andersson, Tommy B.
    Karlén, Anders
    Masimirembwa, Collen
    Competitive CYP2C9 Inhibitors: Enzyme inhibition Studies, Protein Homology Modelling, and Three-Dimensional Quantitative Structure Activity Relationship Analysis2001In: Molecular Pharmacology, ISSN 0026-895, Vol. 59, p. 909 - 919Article in journal (Refereed)
  • 32.
    Agalo, Faith
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Synthesis of Insulin-Regulated Aminopeptidase (IRAP) inhibitors2015Independent thesis Advanced level (professional degree), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    The need for alternative cognitive enhancers has risen due to the fact that clinical trial results of the drugs currently approved for treating these disorders have not been satisfactory.

    IRAP has become a possible drug target for treating cognitive impairment brought about by Alzheimer’s disease, head trauma or cerebral ischemia, among others. This came after the revelation that Angiotensin IV enhances memory and learning. Angiotensin IV, the endogenous ligand of IRAP has been structurally modified with the aim of producing potent IRAP inhibitors. However, the peptidic nature of these inhibitors restricts their use; they are not likely to cross the blood brain barrier.

    Other strategies for generating IRAP inhibitors have been through structure-based design and receptor based virtual screening. These drug-like molecules have exhibited positive results in animal studies.

    IRAP inhibitors have been identified via a HTS of 10500 low-molecular weight compounds to give the hit based on a spirooxindole dihydroquinazolinone scaffold, with an IC50 value of 1.5 µM. In this project, some analogues to this hit compound have successfully been synthesized using a known method, whereas others have been synthesized after additional method development.

    The application of the developed method was found to be limited, because poor yield was obtained when a compound with an electron withdrawing substituent on the aniline was synthesized. As a result of this, modification of this method may be required or new methods may have to be developed to synthesize these types of analogues.

    Inhibition capability of 5 new spirooxindole dihydroquinazolinones was tested through a biochemical assay. Compound 6e emerged as the most potent inhibitor in the series, with an IC50 value of 0.2 µM. This compound will now serve as a lead compound and should be used as a starting point for future optimization in order to generate more potent IRAP inhibitors.

     

  • 33.
    Ahlgren, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Remediation of diclofenac in a non-sterile bioreactor using the white rot fungus Trametes versicolor2015Independent thesis Advanced level (professional degree), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    From an environmental perspective, it is interesting to assess new methods for efficient removal of drugs from wastewater. The purpose of this project was to assess the possibility of using the white rot fungus Trametes versicolor  to degrade diclofenac in a lab scale bioreactor. Two methods for quantitative analysis of diclofenac were developed, using GC-MS and UHPLC-Q-TOF (C18-column). Both methods were partly validated, with regard to sensitivity, linearity, accuracy and precision, which highlighted the superiority of UHPLC-Q-TOF over GC-MS. Two HILIC columns were also assessed, but proved unsuitable for quantitative analysis of diclofenac under the used conditions. The fungal mycelia were immobilized on plastic carriers in a nutrient solution. In initial E-flask experiments, 10 mg/L diclofenac was added to an active culture and a heat-killed control of T. versicolor . Samples were analyzed, and the results from the active culture indicated a 98% removal of diclofenac after 48 hours. The lab scale bioreactor was used in a semi-continuous mode with the influent containing 10 mg/L diclofenac. Samples were collected from the effluent to monitor the concentration over 7 days. The results showed a decline in concentration to a stable level of approximately 2 mg/L. The initial experiments showed that most of the removal (85%) was due to sorption of diclofenac, but a clear difference was seen between the active and heat-killed culture. It was impossible to conclude from the bioreactor experiment if the observed removal was due to sorption or to a combination of sorption and enzymatic remediation.

  • 34. Ahlström, Katarina
    et al.
    Biber, Björn
    Åberg, Anna-Maja
    Abrahamsson, Pernilla
    Johansson, Göran
    Ronquist, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Waldenström, Anders
    Haney, Michael F.
    Exogenous carbon monoxide does not affect cell membrane energy availability assessed by sarcolemmal calcium fluxes during myocardial ischaemia-reperfusion in the pig2011In: European Journal of Anaesthesiology, ISSN 0265-0215, E-ISSN 1365-2346, Vol. 28, no 5, p. 356-362Article in journal (Refereed)
    Abstract [en]

    Carbon monoxide is thought to be cytoprotective and may hold therapeutic promise for mitigating ischaemic injury. The purpose of this study was to test low-dose carbon monoxide for protective effects in a porcine model of acute myocardial ischaemia and reperfusion. In acute open-thorax experiments in anaesthetised pigs, pretreatment with low-dose carbon monoxide (5% increase in carboxyhaemoglobin) was conducted for 120 min before localised ischaemia (45 min) and reperfusion (60 min) was performed using a coronary snare. Metabolic and injury markers were collected by microdialysis sampling in the ventricular wall. Recovery of radio-marked calcium delivered locally by microperfusate was measured to assess carbon monoxide treatment effects during ischaemia/reperfusion on the intracellular calcium pool. Coronary occlusion and ischaemia/reperfusion were analysed for 16 animals (eight in each group). Changes in glucose, lactate and pyruvate from the ischaemic area were observed during ischaemia and reperfusion interventions, though there was no difference between carbon monoxide-treated and control groups during ischaemia or reperfusion. Similar results were observed for glycerol and microdialysate Ca-45(2+) recovery. These findings show that a relatively low and clinically relevant dose of carbon monoxide did not seem to provide acute protection as indicated by metabolic, energy-related and injury markers in a porcine myocardial ischaemia/reperfusion experimental model. We conclude that protective effects of carbon monoxide related to ischaemia/reperfusion either require higher doses of carbon monoxide or occur later after reperfusion than the immediate time frame studied here. More study is needed to characterise the mechanism and time frame of carbon monoxide-related cytoprotection.

  • 35.
    Ahlsén, Göran