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  • 1.
    Adrian Meredith, Jenny
    et al.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Björklund, Catarina
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Adolfsson, Hans
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Edlund, Michael
    Jansson, Katarina
    Lindberg, Jimmy
    Vrang, Lotta
    Hallberg, Anders
    Institutionen för läkemedelskemi, Uppsala universitet.
    Rosenquist, Åsa
    Samuelsson, Bertil
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Design and Synthesis of BACE-1 Inhibitors Containing a New Hydroxyethylene (HE) Scaffold: Potent activities in a cellular assayManuscript (preprint) (Other academic)
    Abstract [en]

    In a preceding report from our group we disclosed the development of a novel HE transition state isostere with a difluorophenoxymethyl side chain in the P1 position and a methoxy group in the P1’ position furnishing highly potent inhibitors of BACE-1 (i.e. lead compound 1), which moreover exhibit very promising selectivity over cathepsin D. In a continuation of this work with the aim at improving on the cell-based activity and pharmacokinetic properties, we have further developed the SAR for the P1 side chain of inhibitor 1 whereby the P1 side chain oxygen has been substituted for an amine, a carbon or a bond. The chemistry developed for the previous HE inhibitor structure 1 has now been extended to readily accommodate the introduction of new P1 side chains into this new HE scaffold. These modifications have given rise to several highly potent inhibitors where the most potent displayed a BACE-1 Ki value of 0.2 nM and a cell-based Aβ40 IC50 value of 9 nM. Thus, regarding the enzyme inhibition in the cell assay a more than 600-fold improvement compared to compound 1 was achieved via minor structural alterations.

  • 2.
    Adrian Meredith, Jenny
    et al.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Björklund, Catarina
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Adolfsson, Hans
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Jansson, Katarina
    Hallberg, Anders
    Institutionen för läkemedelskemi, Uppsala universitet.
    Rosenquist, Åsa
    Samuelsson, Bertil
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    P2’-truncated BACE-1 inhibitors with a novel hydroxethylene-like core2010In: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 45, no 2, p. 542-554Article in journal (Refereed)
    Abstract [en]

    Highly potent BACE-1 protease inhibitors derived from a novel hydroxyethylene-like core structure were recently developed by our group using X-ray crystal structure data and molecular modelling. In a continuation of this work guided by molecular modelling we have explored a truncated core motif where the P2’ amide group is replaced by an ether linkage resulting in a set of alkoxy, aryloxy and alkylaryl groups, with the overall aim to reduce molecular weight and the number of amide bonds to increase permeability and bestow the inhibitors with drug-like features. The most potent of these inhibitors displayed a BACE-1 IC50 value of 140 nM. The synthesis of these BACE-1 inhibitors utilizes readily available starting materials, furnishing the target compounds in good overall yields.

  • 3.
    Adrian Meredith, Jenny
    et al.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Wallberg, Hans
    Vrang, Lotta
    Oscarson, Stefan
    Centre for Synthesis and Chemical Biology, University College Dublin, Belfield, Dublin 4, Ireland.
    Parkes, Kevin
    Hallberg, Anders
    Institutionen för läkemedelskemi, Uppsala universitet.
    Samuelsson, Bertil
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Design and Synthesis of Novel P2 Substituents in Diol-based HIV Protease Inhibitors2010In: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 45, no 1, p. 160-170Article in journal (Refereed)
    Abstract [en]

    The synthesis and SAR of HIV-1 protease inhibitors containing novel P2 structural elements are presented. The inhibitors were designed having hydrogen bond accepting P2 substituents to probe potential favorable interactions to Asp-29/Asp-30 of the HIV-1 protease backbone utilizing inhibitor 3 as a model template. Several inhibitors were synthesized from an L-Val-methylamide P2 motif by appending hydrogen bonding moieties from either the isopropyl side chain or from the methylamide portion. The most promising inhibitors 4a and 4e displayed Ki values of 1.0 nM and 0.7 nM respectively and EC50 values in the MT4 cell-based assay of 0.17 µM and 0.33 µM respectively, a slight loss in potency compared to lead inhibitor 3. These inhibitors were also tested against an HIV protease inhibitor resistant strain carrying the M46I, V82F, and I84V mutations. Inhibitors 4a and 4e displayed a 3 and 4 fold change respectively compared with HIV wild type, whereas lead inhibitor 3 showed a higher 9 fold change. This study further demonstrate the chemical tractability of the approach where various P2 substituents can be introduced in just one chemical step from lactone x enabling facile modifications of the overall properties in this inhibitor class.

  • 4.
    Ayesa, Susana
    et al.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Lindquist, Charlotta
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Agback, Tatiana
    Benkestock, Kurt
    Classon, Björn
    Henderson, Ian
    Hewitt, Ellen
    Jansson, Katarina
    Kallin, Anders
    Sheppard, Dave
    Samuelsson, Bertil
    Solid-phase parallel synthesis and SAR of 4-amidofuran-3-one inhibitors of cathepsin S: Effect of sulfonamides P3 substituents on potency and selectivity.2009In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 17, no 3, p. 1307-1324Article in journal (Refereed)
    Abstract [en]

    Highly potent and selective 4-amidofuran-3-one inhibitors of cathepsin S are described. The synthesis and structure–activity relationship of a series of inhibitors with a sulfonamide moiety in the P3 position is presented. Several members of the series show sub-nanomolar inhibition of the target enzyme as well as an excellent selectivity profile and good cellular potency. Molecular modeling of the most interesting inhibitors describes interactions in the extended S3 pocket and explains the observed selectivity towards cathepsin K.

  • 5. Barlind, Jonas G.
    et al.
    Buckett, Linda K.
    Crosby, Sharon G.
    Davidsson, Ojvind
    Emtenas, Hans
    Ertan, Anne
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
    Jurva, Ulrik
    Lemurell, Malin
    Gutierrez, Pablo Morentin
    Nilsson, Karolina
    O'Mahony, Gavin
    Petersson, Annika U.
    Redzic, Alma
    Wagberg, Fredrik
    Yuan, Zhong-Qing
    Identification and design of a novel series of MGAT2 inhibitors2013In: Bioorganic & Medicinal Chemistry Letters, ISSN 0960-894X, E-ISSN 1090-2120, Vol. 23, no 9, p. 2721-2726Article in journal (Refereed)
    Abstract [en]

    [Acyl CoA]monoacylglycerol acyltransferase 2 (MGAT2) is of interest as a target for therapeutic treatment of diabetes, obesity and other diseases which together constitute the metabolic syndrome. In this Letter we report our discovery and optimisation of a novel series of MGAT2 inhibitors. The development of the SAR of the series and a detailed discussion around some key parameters monitored and addressed during the lead generation phase will be given. The in vivo results from an oral lipid tolerance test (OLTT) using the MGAT2 inhibitor (S)-10, shows a significant reduction (68% inhibition relative to naive, p < 0.01) in plasma triacylglycerol (TAG) concentration.

  • 6. Bjorklund, Geir
    et al.
    Stejskal, Vera
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Urbina, Mauricio A.
    Dadar, Maryam
    Chirumbolo, Salvatore
    Mutter, Joachim
    Metals and Parkinson's Disease: Mechanisms and Biochemical Processes2018In: Current Medicinal Chemistry, ISSN 0929-8673, E-ISSN 1875-533X, Vol. 25, no 19, p. 2198-2214Article, review/survey (Refereed)
    Abstract [en]

    Genetic background accounts for only 5 to 10% of the reported cases of Parkinson's disease (PD), while the remaining cases are of unknown etiology. It is believed that environmental factors may be involved in the causality of a large proportion of PD cases. Several PD genes are activated by xenobiotic exposure, and a link between pesticide exposure and PD has been demonstrated. Many epidemiological studies have shown an association between PD and exposure to metals such as mercury, lead, manganese, copper, iron, aluminum, bismuth, thallium, and zinc. This review explores the biological effects, the pathogenetic processes, genetic susceptibilities to metals as well as examining future strategies for PD treatment, such as chelation therapy.

  • 7.
    Björklund, Catarina
    et al.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Adolfsson, Hans
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Jansson, Katarina
    Lindberg, Jimmy
    Vrang, Lotta
    Hallberg, Anders
    Rosenquist, Åsa
    Samuelsson, Bertil
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Discovery of Potent BACE-1 Inhibitors Containing a New Hydroxyethylene (HE) Scaffold: Exploration of P1’ Alkoxy Residues and an Aminoethylene (AE) Central Core2010In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 18, no 4, p. 1711-1723Article in journal (Refereed)
    Abstract [en]

    In a preceding study we have described the development of a new hydroxyethylene (HE) core motif displaying P1 aryloxymethyl and P1’ methoxy substituents delivering potent BACE-1 inhibitors. In a continuation of this work we have now explored the SAR of the S1’ pocket by introducing a set of P1’ alkoxy groups and evaluated them as BACE-1 inhibitors. Previously the P1 and P1’ positions of the classical HE template have been relatively little explored due to the complexity of the chemical routes involved in modifications at these positions. However, the chemistries developed for the current HE template renders substituents in both the P1 and P1’ positions readily available for SAR exploration. The BACE-1 inhibitors prepared displayed IC50 values in the range of 4-45 nM, where the most potent compounds featured small P1’ groups. The cathepsin D selectivity which was high for the smallest P1’ sustituents (P1’=ethoxy, fold selectively >600) dropped for larger groups (P1’=benzyloxy, fold selectivity of 1.6). We have also confirmed the importance of both the hydroxyl group and its stereochemistry preference for this HE transition state isostere by preparing both the deoxygenated analogue and by inverting the configuration of the hydroxyl group to the R-configuration, which as expected resulted in large activity drops. Finally substituting the hydroxyl group by an amino group having the same configuration (S), which previously have been described to deliver potent BACE-1 inhibitors with advantageous properties, surprisingly resulted in a large drop in the inhibitory activity.

  • 8.
    Björklund, Catarina
    et al.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Oscarson, Stefan
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Benkestock, Kurt
    Borkakoti, Neera
    Jansson, Katarina
    Lindberg, Jimmy
    Vrang, Lotta
    Hallberg, Anders
    Rosenquist, Åsa
    Samuelsson, Bertil
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Design and synthesis of potent and selective BACE-1 inhibitors2010In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 53, no 4, p. 1458-1464Article in journal (Refereed)
    Abstract [en]

    Several highly potent BACE-1 protease inhibitors have been developed from an inhibitor series containing a novel hydroxyethylene (HE) core structure displaying aryloxymethyl or benzyloxymethyl P1 side chains and a methoxy P1’ side chain. The target molecules were readily synthesized from chiral carbohydrate starting materials, furnishing the inhibitor compounds in good overall yields. The inhibitors show both high BACE-1 potency and good selectivity against cathepsin D, where the most potent inhibitor furnish a BACE-1 IC50 value of 0.32 nM and displays > 3000 fold selectivity over cathepsin D.

  • 9. Ertan-Bolelli, Tugba
    et al.
    Bolelli, Kayhan
    Musdal, Yaman
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Yildiz, Ilkay
    Aki-Yalcin, Esin
    Mannervik, Bengt
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Yalcin, Ismail
    Design and synthesis of 2-substituted-5-(4-trifluoromethylphenyl-sulphonamido)benzoxazole derivatives as human GST P1-1 inhibitors2018In: Artificial Cells, Nanomedicine, and Biotechnology, ISSN 2169-1401, Vol. 46, no 3, p. 510-517Article in journal (Refereed)
    Abstract [en]

    The glutathione transferases (GSTs) are a family of widely distributed Phase II detoxification enzymes. GST P1-1 is frequently overexpressed in rat and human tumours. It is suggested that overexpression of hGST P1-1 by human tumor cells may play a role in resistance to cancer chemotherapy. Hence, hGST P1-1 can be a promising target for cancer treatment. In this study, new hGST P1-1 inhibitors, 2-(4-substitutedphenyl/benzyl)-5-(4-trifluoromethylphenylsulphonamido) benzoxazole derivatives (Va-Vk) have been designed and synthesized. Surprisingly, in vitro hGST P1-1 enzyme inhibition studies demonstrated that all of the tested compounds except Vj had better activity than the reference drug EA and it is also correlated with the docking results. Additionally we compared the interactions with hGST P1-1 enzyme of newly synthesized compound Vh (bearing CF3 group) and previously synthesized compound 5f (bearing NO2 group). According to the docking results, compound Vh bound to the hGST P1-1 enzyme with a higher affinity compared to 5f. Therefore, we can consider that these data make a sense and can explain its higher activity. The compounds that obtained from this research could be used as scaffolds in design of new potent hGST P1-1 inhibitors useful in the treatment of the resistance of cancer chemotherapy.

  • 10.
    Heusser, Stephanie A.
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Yoluk, Özge
    Klement, Göran
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Riederer, Erika A.
    Lindahl, Erik
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab). KTH Royal Institute of Technology, Sweden.
    Howard, Rebecca J.
    Functional characterization of neurotransmitter activation and modulation in a nematode model ligand-gated ion channel2016In: Journal of Neurochemistry, ISSN 0022-3042, E-ISSN 1471-4159, Vol. 138, no 2, p. 243-253Article in journal (Refereed)
    Abstract [en]

    The superfamily of pentameric ligand-gated ion channels includes neurotransmitter receptors that mediate fast synaptic transmission in vertebrates, and are targets for drugs including alcohols, anesthetics, benzodiazepines, and anticonvulsants. However, the mechanisms of ion channel opening, gating, and modulation in these receptors leave many open questions, despite their pharmacological importance. Subtle conformational changes in both the extracellular and transmembrane domains are likely to influence channel opening, but have been difficult to characterize given the limited structural data available for human membrane proteins. Recent crystal structures of a modified Caenorhabditis elegans glutamate-gated chloride channel (GluCl) in multiple states offer an appealing model system for structure-function studies. However, the pharmacology of the crystallographic GluCl construct is not well established. To establish the functional relevance of this system, we used two-electrode voltage-clamp electrophysiology in Xenopus oocytes to characterize activation of crystallographic and native-like GluCl constructs by L-glutamate and ivermectin. We also tested modulation by ethanol and other anesthetic agents, and used site-directed mutagenesis to explore the role of a region of Loop F which was implicated in ligand gating by molecular dynamics simulations. Our findings indicate that the crystallographic construct functionally models concentration-dependent agonism and allosteric modulation of pharmacologically relevant receptors. Specific substitutions at residue Leu174 in loop F altered direct L-glutamate activation, consistent with computational evidence for this region's role in ligand binding. These insights demonstrate conservation of activation and modulation properties in this receptor family, and establish a framework for GluCl as a model system, including new possibilities for drug discovery. In this study, we elucidate the validity of a modified glutamate-gated chloride channel (GluCl(cryst)) as a structurally accessible model for GABA(A) receptors. In contrast to native-like controls, GluCl(cryst) exhibits classical activation by its neurotransmitter ligand L-glutamate. The modified channel is also sensitive to allosteric modulators associated with human GABA(A) receptors, and to site-directed mutations predicted to alter channel opening.

  • 11. Kiss, Anita
    et al.
    Herman, Bianka Edina
    Görbe, Tamás
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Mernyak, Erzsebet
    Molnar, Barnabas
    Wolfling, Janos
    Szecsi, Mihaly
    Schneider, Gyula
    Synthesis of novel 17-triazolyl-androst-5-en-3-ol epimers via Cu(I)-catalyzed azide-alkyne cycloaddition and their inhibitory effect on 17 alpha-hydroxylase/ C-17,C-20-lyase2018In: Steroids, ISSN 0039-128X, E-ISSN 1878-5867, Vol. 135, p. 79-91Article in journal (Refereed)
    Abstract [en]

    The regioselective Cu(I)-catalyzed 1,3-dipolar cycloaddition of 17 alpha- and 17 beta-azidoandrost-5-en-3 beta-ol epimers (3b and 5b) with different terminal alkynes afforded novel 1,4-substituted triazolyl derivatives (8a-k and 9a-k). For the preparation of 5'-iodo-l',2',3'-triazoles (8m-n and 9m-n), an improved method was developed, directly from steroidal azides and terminal alkynes, in reaction mediated by Cul and IC1 as iodinating agents. Acetolysis and subsequent hydrolysis of 8n and 9n yielded 5'-hydroxy-l',2',3'-triazoles 8o and 9o. The inhibitory effect of 8a-o, 9a-o, 3, and 5 on rat testicular C-17,C-20-lyase was investigated by means of an in vitro radioincubation technique. The results revealed that the C-17 epimers of steroidal triazoles influence the C-17,C-20-lyase effect. Inhibitors were found only in the 17 alpha-triazolyl series (8a-o), whereas in the C-17 azide pair the 17 beta compound (5b) was more potent.

  • 12. Kurrikoff, Kaido
    et al.
    Gestin, Maxime
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Langel, Ülo
    Stockholm University, Faculty of Science, Department of Neurochemistry. University of Tartu, Estonia.
    Recent in vivo advances in cell-penetrating peptide-assisted drug delivery2016In: Expert Opinion on Drug Delivery, ISSN 1742-5247, E-ISSN 1744-7593, Vol. 13, no 3, p. 373-387Article, review/survey (Refereed)
    Abstract [en]

    Introduction: Delivery of macromolecular drugs is an important field in medical research. However, macromolecules are usually unable to cross the cell membrane without the assistance of a delivery system. Cell penetrating peptides (CPPs) are unique tools to gain access to the cell interior and deliver a bioactive cargo into the cytosol or nucleus. In addition to macromolecular delivery, CPPs have been used to deliver smaller bioactive molecules. Therefore CPPs have become an intensive field of research for medical treatment.

    Areas covered: In this review, we highlight studies that include CPP in vivo disease models. We review different strategies and approaches that have been used, with specific attention on recent publications. The approaches that have been used include CPP–cargo covalent conjugation strategies and nanoparticle strategies. Various additional strategies have been used to achieve disease targeting, including active targeting, passive targeting, and combined active/passive strategies. As a result, delivery of various types of molecule has been achieved, including small drug molecules, proteins and nucleic acid-based macromolecules (e.g. siRNA, antisense nucleotides and plasmid DNA).

    Expert Opinion: Despite recent advances in the field, confusions surrounding CPP internalization mechanisms and intracellular trafficking are hindering the development of new and more efficient vectors. Nevertheless, the recent increase in the number of publications containing in vivo CPP utilization looks promising that the number of clinical trials would also increase in the near future.

  • 13. Llona-Minguez, Sabin
    et al.
    Höglund, Andreas
    Jacques, Sylvain A.
    Johanson, Lars
    Calderon-Montano, Jose Manuel
    Claesson, Magnus
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Loseva, Olga
    Valerie, Nicholas C. K.
    Lundbäck, Thomas
    Piedrafita, Javier
    Maga, Giovanni
    Crespan, Emmanuele
    Meijer, Laurent
    Burgos Moron, Estefania
    Baranczewski, Pawel
    Hagbjörk, Ann-Louise
    Svensson, Richard
    Wiita, Elisee
    Almlöf, Ingrid
    Visnes, Torkild
    Jeppsson, Fredrik
    Sigmundsson, Kristmundur
    Jenmalm Jensen, Annika
    Artursson, Per
    Jemth, Ann-Sofie
    Stenmark, Pål
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Warpman Berglund, Ulrika
    Scobie, Martin
    Helleday, Thomas
    Discovery of the First Potent and Selective Inhibitors of Human dCTP Pyrophosphatase 12016In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 59, no 3, p. 1140-1148Article in journal (Refereed)
    Abstract [en]

    The dCTPase pyrophosphatase 1 (dCTPase) regulates the intracellular nucleotide pool through hydrolytic degradation of canonical and noncanonical nucleotide triphosphates (dNTPs). dCTPase is highly expressed in multiple carcinomas and is associated with cancer cell sternness. Here we report on the development of the first potent and selective dCTPase inhibitors that enhance the cytotoxic effect of cytidine analogues in leukemia cells. Boronate 30 displays a promising in vitro ADME profile, including plasma and mouse microsomal half-lives, aqueous solubility, cell permeability and CYP inhibition, deeming it a suitable compound for in vivo studies.

  • 14. Llona-Minguez, Sabin
    et al.
    Höglund, Andreas
    Wiita, Elisee
    Almlöf, Ingrid
    Mateus, Andre
    Calderon-Montano, Jose Manuel
    Cazares-Körner, Cindy
    Homan, Evert
    Loseva, Olga
    Baranczewski, Pawel
    Jemth, Ann-Sofie
    Häggblad, Maria
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Martens, Ulf
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Lundgren, Bo
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Artursson, Per
    Lundbäck, Thomas
    Jenmalm Jensen, Annika
    Warpman Berglund, Ulrika
    Scobie, Martin
    Helleday, Thomas
    Identification of Triazolothiadiazoles as Potent Inhibitors of the dCTP Pyrophosphatase 12017In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 60, no 5, p. 2148-2154Article in journal (Refereed)
    Abstract [en]

    The dCTP pyrophosphatase 1 (dCTPase) is involved in the regulation of the cellular dNTP pool and has been linked to cancer progression. Here we report on the discovery of a series of 3,6-disubstituted triazolothiadiazoles as potent dCTPase inhibitors. Compounds 16 and 18 display good correlation between enzymatic inhibition and target engagement, together with efficacy in a cellular synergy model, deeming them as a promising starting point for hit -to-lead development.

  • 15. Nilsson, Magnus
    et al.
    Belfrage, Anna Karin
    Lindström, Stefan
    Wähling, Horst
    Lindquist, Charlotta
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Ayesa Alvarez, Susana
    Kahnberg, Pia
    Pelcman, Mikael
    Vrang, Lotta
    Terselius, Ylva
    Wikström, Kristina
    Hamelink, Elizabeth
    Rydergård, Christina
    Edlund, Michael
    Eneroth, Anders
    Raboisson, Pierre
    Lin, Tse-I.
    de Kock, Herman
    Wigerinck, Piet
    Simmen, Kenneth
    Samuelsson, Bertil
    Rosenquist, Åsa
    Synthesis and SAR of potent inhibitors of the Hepatitis C virus NS3/4A protease: exploration of P2 quinazoline substituents.Manuscript (preprint) (Other academic)
    Abstract [en]

    Novel NS3/4A protease inhibitors comprising quinazoline derivatives as P2 substituent were synthesized. High potency inhibitors displaying advantageous PK properties have been obtained through the optimization of quinazoline P2 substituents in three series of macrocyclic P2 cyclopentane dicarboxylic acid and P2 proline urea motifs. For the quinazoline moiety it was found that 8-methyl substitution for the P2 cyclopentane dicarboxylic acid series improved on the stability in human liver microsomes. By comparison, the proline urea series displayed advantageous Caco-2 permeability over the cyclopentane series. properties were assessed in rat on selected compounds. Excellent exposure and liver–to-plasma ratios were demonstrated for a member of the 14-membered quinazoline substituted P2 proline urea series. In vivo pharmacokinetic properties were assessed in rat on selected compounds. Excellent exposure and liver–to-plasma ratios were demonstrated for a member of the 14-membered quinazoline substituted P2 proline urea series.

  • 16.
    Ranganathan, Anirudh
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Stoddart, Leigh A.
    Hill, Stephen J.
    Carlsson, Jens
    Fragment-Based Discovery of Subtype-Selective Adenosine Receptor Ligands from Homology Models2015In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 58, no 24, p. 9578-9590Article in journal (Refereed)
    Abstract [en]

    Fragment-based lead discovery (FBLD) holds great promise for drug discovery, but applications to G protein-coupled receptors (GPCRs) have been limited by a lack of sensitive screening techniques and scarce structural information. If virtual screening against homology models of GPCRs could be used to identify fragment ligands, FBLD could be extended to numerous important drug targets and contribute to efficient lead generation. Access to models of multiple receptors may further enable the discovery of fragments that bind specifically to the desired target. to investigate these questions, we used molecular docking, to screen >500 000 fragments against homology models. of the A(3) and A(1) adenosine receptors (ARs) with the goal to discover,A(3)AR-selective ligands. Twenty-one fragments with predicted A(3)AR-specific binding were evaluated in live-cell fluorescence-based assays; of eight verified ligands, six displayed A(3)/A(1), selectivity,, and three of these had high affinities ranging from 0.1 to 1.3 mu M. Subsequently, structure-guided fragment-to-lead optimization led to the identification of a >100-fold-selective antagonist with nanomolar affinity from commercial libraries. These results highlight that molecular docking screening can guide fragment-based discovery of selective ligands even if the Structures of both the target and antitarget receptors are unknown. The same approach can be readily extended to a large number of pharmaceutically important targets.

  • 17.
    Rodríguez, David
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab). SeRC, Sweden.
    Ranganathan, Anirudh
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab). SeRC, Sweden.
    Carlsson, Jens
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab). SeRC, Sweden.
    Discovery of GPCR Ligands by Molecular Docking Screening: Novel Opportunities Provided by Crystal Structures2015In: Current Topics in Medicinal Chemistry, ISSN 1568-0266, E-ISSN 1873-4294, Vol. 15, no 24, p. 2484-2503Article, review/survey (Refereed)
    Abstract [en]

    G protein-coupled receptors (GPCRs) constitute the largest group of human membrane proteins and have received significant attention in drug discovery for their important roles in physiological processes. Drug development for GPCRs has been remarkably successful and several of the most profitable pharmaceuticals on the market target members of this superfamily. Breakthroughs in structural biology for GPCRs have revealed how their binding sites recognize extracellular molecules at the atomic level. High-resolution crystal structures of GPCR-drug complexes capturing different receptor conformations are now available, which have provided insights into how ligands stabilize different functional states. Recently, the basis for subtype selectivity and novel allosteric binding sites has also been revealed by crystal structures. These accomplishments provide exciting opportunities to identify novel GPCR ligands using in silico structure-based methods such as molecular docking. Increased computational power now enables docking screens of large chemical libraries to identify molecules that complement GPCR binding sites, which may provide possibilities to identify ligands with tailored pharmacological properties. This review focuses on prospective docking screens against GPCRs and how this technique can be used to identify lead candidates with specific signaling or selectivity profiles. The current state of this field suggests that molecular docking, in combination with further understanding of GPCR signaling, will play an important role in future drug discovery.

  • 18.
    Runesson, Johan
    et al.
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Saar, Indrek
    Sillard, Rannar
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Langel, Ülo
    Stockholm University, Faculty of Science, Department of Neurochemistry. University of Tartu, Estonia.
    M1154 – A novel galanin ligand to delineate the galaninergic system2010In: Peptides 2010: Proceedings of the European Peptide Symposium / [ed] Michal Lebl, Morten Meldal, Knud J. Jensen, Thomas Høeg-Jensen, European Peptide Society and PSP , 2010Conference paper (Other academic)
    Abstract [en]

    The galanin family currently consists of four members, namely galanin, galanin-message-associated peptide (GMAP), galanin-like peptide (GALP) and alarin. The galanin peptide family and its three receptors (GalR1-3) have with compelling evidence been implicated in a variety of human disorders. The co-localization with other neuromodulators and the distinct up-regulation during and after pathological disturbances has drawn attention to this neuropeptide family. Here we present data on receptor binding and preliminary data in functional response for the novel M1154 peptide, including a comparison with several GalR2 selective peptides. M1154 retains high affinity binding to GalR1 and GalR2 although it has no detectable binding to GalR3. We believe that utilizing this selective galanin ligand together with previous published M1145 raise the possibility to delineate the galanin system.

     

  • 19.
    Smirnova, Anna
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Wincent, Emma
    Vikström Bergander, Linda
    Alsberg, Tomas
    Stockholm University, Faculty of Science, Department of Applied Environmental Science (ITM).
    Bergman, Jan
    Rannug, Agneta
    Rannug, Ulf
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Evidence for New Light-Independent Pathways for Generation of the Endogenous Aryl Hydrocarbon Receptor Agonist FICZ2016In: Chemical Research in Toxicology, ISSN 0893-228X, E-ISSN 1520-5010, Vol. 29, no 1, p. 75-86Article in journal (Refereed)
    Abstract [en]

    Activation of the aryl hydrocarbon receptor (AhR), a conserved transcription factor best known as a target for highly toxic halogenated substances such as dioxin, under normal xenobiotic-free conditions is of considerable scientific interest. We have demonstrated previously that a photoproduct of tryptophan, 6-formylindolo[3,2-b]carbazole (FICZ), fulfills the criteria for an endogenous ligand for this receptor and proposed that this compound is the enigmatic mediator of the physiological functions of AhR. Here, we describe novel light-independent pathways by which FICZ can be formed. The oxidant H2O2 was shown to convert tryptophan to FICZ on its own in the absence of light. The enzymatic deamination of tryptamine yielded indole-3-acetaldehyde (I3A), which then rearranged to FICZ and its oxidation product, indolo[3,2-b]carbazole-6-carboxylic acid (CICZ). Indole-3-pyruvate (I3P) also produced I3A, FICZ, and CICZ. Malassezia yeast species, which constitute a part of the normal skin microbiota, produce a number of AhR activators from tryptophan. We identified both FICZ and CICZ among those products. Formation of FICZ from tryptophan or I3P produces a complex mixture of indole derivatives, some of which are CYP1A1 inhibitors. These can hinder the cellular clearance of FICZ and thereby increase its power as an AhR agonist. We present a general molecular mechanism involving dehydrogenations and oxidative coupling for the formation of FICZ in which I3A is the important precursor. In conclusion, our results suggest that FICZ is likely to be formed systemically.

  • 20. Wacker, Soeren J.
    et al.
    Jurkowski, Wiktor
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Simmons, Katie J.
    Fishwick, Colin W. G.
    Johnson, A. Peter
    Madge, David
    Lindahl, Erik
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Rolland, Jean-Francois
    de Groot, Bert L.
    Identification of Selective Inhibitors of the Potassium Channel Kv1.1-1.2(3) by High-Throughput Virtual Screening and Automated Patch Clamp2012In: ChemMedChem, ISSN 1860-7179, E-ISSN 1860-7187, Vol. 7, no 10, p. 1775-1783Article in journal (Refereed)
    Abstract [en]

    Two voltage-dependent potassium channels, Kv1.1 (KCNA1) and Kv1.2 (KCNA2), are found to co-localize at the juxtaparanodal region of axons throughout the nervous system and are known to co-assemble in heteromultimeric channels, most likely in the form of the concatemer Kv1.11.2(3). Loss of the myelin sheath, as is observed in multiple sclerosis, uncovers the juxtaparanodal region of nodes of Ranvier in myelinated axons leading to potassium conductance, resulting in loss of nerve conduction. The selective blocking of these Kv channels is therefore a promising approach to restore nerve conduction and function. In the present study, we searched for novel inhibitors of Kv1.11.2(3) by combining a virtual screening protocol and electrophysiological measurements on a concatemer Kv1.11.2(3) stably expressed in Chinese hamster ovary K1 (CHO-K1) cells. The combined use of four popular virtual screening approaches (eHiTS, FlexX, Glide, and Autodock-Vina) led to the identification of several compounds as potential inhibitors of the Kv1.11.2(3) channel. From 89 electrophysiologically evaluated compounds, 14 novel compounds were found to inhibit the current carried by Kv1.11.2(3) channels by more than 80?% at 10 mu M. Accordingly, the IC50 values calculated from concentrationresponse curve titrations ranged from 0.6 to 6 mu M. Two of these compounds exhibited at least 30-fold higher potency in inhibition of Kv1.11.2(3) than they showed in inhibition of a set of cardiac ion channels (hERG, Nav1.5, and Cav1.2), resulting in a profile of selectivity and cardiac safety. The results presented herein provide a promising basis for the development of novel selective ion channel inhibitors, with a dramatically lower demand in terms of experimental time, effort, and cost than a sole high-throughput screening approach of large compound libraries.

  • 21. Zhu, Yafeng
    et al.
    Orre, Lukas M.
    Johansson, Henrik J.
    Huss, Mikael
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Boekel, Jorrit
    Vesterlund, Mattias
    Fernandez-Woodbridge, Alejandro
    Branca, Rui M. M.
    Lehtiö, Janne
    Discovery of coding regions in the human genome by integrated proteogenomics analysis workflow2018In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 9, article id 903Article in journal (Refereed)
    Abstract [en]

    Proteogenomics enable the discovery of novel peptides (from unannotated genomic protein-coding loci) and single amino acid variant peptides (derived from single-nucleotide polymorphisms and mutations). Increasing the reliability of these identifications is crucial to ensure their usefulness for genome annotation and potential application as neoantigens in cancer immunotherapy. We here present integrated proteogenomics analysis workflow (IPAW), which combines peptide discovery, curation, and validation. IPAW includes the SpectrumAI tool for automated inspection of MS/MS spectra, eliminating false identifications of single-residue substitution peptides. We employ IPAW to analyze two proteomics data sets acquired from A431 cells and five normal human tissues using extended (pH range, 3-10) high-resolution isoelectric focusing (HiRIEF) pre-fractionation and TMT-based peptide quantitation. The IPAW results provide evidence for the translation of pseudogenes, lncRNAs, short ORFs, alternative ORFs, N-terminal extensions, and intronic sequences. Moreover, our quantitative analysis indicates that protein production from certain pseudogenes and lncRNAs is tissue specific.

  • 22. Zuber, Bartek
    et al.
    Rudstrom, Karin
    Ehrnfelt, Cecilia
    Ahlborg, Niklas
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology. Mabtech, Sweden.
    Epitope Mapping of Neutralizing Monoclonal Antibodies to Human Interferon-gamma Using Human-Bovine Interferon-gamma Chimeras2016In: Journal of Interferon and Cytokine Research, ISSN 1079-9907, E-ISSN 1557-7465, Vol. 36, no 9, p. 542-551Article in journal (Refereed)
    Abstract [en]

    Our aim was to identify conformational epitopes, recognized by monoclonal antibodies (mAbs) made against human (h) interferon (IFN)-. Based on the mAbs' (n=12) ability to simultaneously bind hIFN- in ELISA, 2 epitope clusters with 5mAbs in each were defined; 2mAbs recognized unique epitopes. Utilizing the mAbs' lack of reactivity with bovine (b) IFN-, epitopes were identified using 7h/bIFN- chimeras where the helical regions (A-F) or the C terminus were substituted with bIFN- residues. Chimeras had a N-terminal peptide tag enabling the analysis of mAb recognition of chimeras in ELISA. The 2mAb clusters mapped to region A and E, respectively; the epitopes of several mAbs also involved additional regions. MAbs in cluster A neutralized, to various degrees, IFN--mediated activation of human cells, in line with the involvement of region A in the IFN- receptor interaction. MAbs mapping to region E displayed a stronger neutralizing capacity although this region has not been directly implicated in the receptor interaction. The results corroborate earlier studies and provide a detailed picture of the link between the epitope specificity and neutralizing capacity of mAbs. They further demonstrate the general use of peptide-tagged chimeric proteins as a powerful and straightforward method for efficient mapping of conformational epitopes.

1 - 22 of 22
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