Soerge Kelm

Publications of Soerge Kelm

• 2-deoxyribose deprives cultured astrocytes of their glutathione.

  Authors: Maike M Schmidt, Helena Greb, Hendrik Koliwer-Brandl, Soerge Kelm, Ralf Dringen

  Neurochemical research. 11/2010; 35(11):1848-56.

  High concentrations of 2-deoxy-D-ribose (2dRib) have been reported to cause oxidative stress and to disturb the glutathione (GSH) metabolism of various cell types. Exposure of astrocyte-rich primaryHigh concentrations of 2-deoxy-D-ribose (2dRib) have been reported to cause oxidative stress and to disturb the glutathione (GSH) metabolism of various cell types. Exposure of astrocyte-rich primary cultures to millimolar concentrations of 2dRib or its stereoisomer 2-deoxy-L-ribose, but not the incubation with ribose, 2-deoxyglucose, glucose, fructose or saccharose, lowered the cellular GSH content in a time and concentration dependent manner. After exposure for 4 h to 30 mM 2dRib the cells contained 2dRib in a concentration of about 24 mM. Under these conditions 2dRib did not compromise cell viability and the ability of the cells to synthesise GSH, nor were the cellular ratio of glutathione disulfide (GSSG) to GSH and the extracellular concentrations of GSH or GSSG increased. These data demonstrate that 2dRib deprives viable cultured astrocytes of GSH and suggest that a cellular reaction of GSH with 2dRib or its metabolites is involved in the deprivation of astrocytic GSH.

• A fragment-based in situ combinatorial approach to identify high-affinity ligands for unknown binding sites.

  Authors: Sachin V Shelke, Brian Cutting, Xiaohua Jiang, Hendrik Koliwer-Brandl, Daniel S Strasser, Oliver Schwardt, Soerge Kelm, Beat Ernst

  Angewandte Chemie (International ed. in English). 08/2010; 49(33):5721-5.

• Kinetic and thermodynamic properties of MAG antagonists.

  Authors: Stefanie Mesch, Katrin Lemme, Hendrik Koliwer-Brandl, Daniel S Strasser, Oliver Schwardt, Soerge Kelm, Beat Ernst

  Carbohydrate research. 03/2010; 345(10):1348-59.

  Paraplegia is caused by injuries of the central nervous system (CNS) and especially young people suffer from these severe consequences as, for example, the loss of motor functions. The lack of repairParaplegia is caused by injuries of the central nervous system (CNS) and especially young people suffer from these severe consequences as, for example, the loss of motor functions. The lack of repair of the injured nerve strands originates from the inhibitory environment for axon regeneration in the CNS. Specific inhibitory proteins block the regrowth of nerve roots. One of these neurite outgrowth inhibitors is the myelin-associated glycoprotein (MAG), which is a member of the Siglec family (sialic acid-binding immunoglobulin-like lectin). In previous studies, we identified potent small molecule MAG antagonists. In this communication, we report new neuraminic acid derivatives modified in the 4- and 5-position, and the influence of various structural modifications on their kinetic and thermodynamic binding properties.

• Low molecular weight antagonists of the myelin-associated glycoprotein: synthesis, docking, and biological evaluation.

  Authors: Stefanie Mesch, Delia Moser, Daniel S Strasser, Antje Kelm, Brian Cutting, Gianluca Rossato, Angelo Vedani, Hendrik Koliwer-Brandl, Matthias Wittwer, Said Rabbani, Oliver Schwardt, Soerge Kelm, Beat Ernst

  Journal of medicinal chemistry. 02/2010; 53(4):1597-615.

  The injured adult mammalian central nervous system is an inhibitory environment for axon regeneration due to specific inhibitors, among them the myelin-associated glycoprotein (MAG), a member of theThe injured adult mammalian central nervous system is an inhibitory environment for axon regeneration due to specific inhibitors, among them the myelin-associated glycoprotein (MAG), a member of the Siglec family (sialic-acid binding immunoglobulin-like lectin). In earlier studies, we identified the lead structure 5, which shows a 250-fold improved in vitro affinity for MAG compared to the tetrasaccharide binding epitope of GQ1balpha (1), the best physiological MAG ligand described so far. By modifying the 2- and 5-position, the affinity of 5 could be further improved to the nanomolar range (-->19a). Docking studies to a homology model of MAG allowed the rationalization of the experimental binding properties. Finally, pharmacokinetic parameters (stability in the cerebrospinal fluid, logD and permeation through the BBB) indicate the drug-like properties of the high-affinity antagonist 19a.

• Binding Epitopes of Gangliosides to their Neuronal Receptor, Myelin-Associated Glycoprotein, from Saturation Transfer Difference NMR.

  Authors: So-Young Shin, Heiko Gäthje, Oliver Schwardt, Gan-Pan Gao, Beat Ernst, Soerge Kelm, Bernd Meyer

  Chembiochem : a European journal of chemical biology. 12/2008;

• Consistent Bioactive Conformation of the Neu5Acalpha(2-->3)Gal Epitope Upon Lectin Binding.

  Authors: Anirban Bhunia, Oliver Schwardt, Heiko Gäthje, Gan-Pan Gao, Soerge Kelm, Andrew J Benie, Milos Hricovini, Thomas Peters, Beat Ernst

  Chembiochem : a European journal of chemical biology. 11/2008;

• Design, Synthesis, and Structure-Affinity Relationships of Novel Series of Sialosides as CD22-Specific Inhibitors.

  Authors: Hajjaj Abdu-Allah, Taichi Tamanaka, Jie Yu, Lu Zhuoyuan, Magesh Sadagopan, Takahiro Adachi, Takeshi Tsubata, Soerge Kelm, Hideharu Ishida, Makoto Kiso

  Journal of medicinal chemistry. 11/2008;

  Sialosides incorporating substituted amides or amines at 9-position of sialic acid moiety have been synthesized and evaluated as CD22 inhibitors. Several derivatives exhibited inhibitory potency inSialosides incorporating substituted amides or amines at 9-position of sialic acid moiety have been synthesized and evaluated as CD22 inhibitors. Several derivatives exhibited inhibitory potency in sub- to low micromolar range (e. g., 8o, 9d, 9g, and 9k showed IC 50 values 0.40, 0.47, 0.24, and 0.23 muM, respectively, for hCD22, while 8p, 8q, and 9f, showed IC 50 values 1.70, 2.90, and 4.10 muM, respectively, for mCD22). The most significant result was the strongly enhanced affinity of 9g and 9k containing 9-(2' or 4'-hydroxy-4-biphenyl) methylamino substituents (600-fold more potent for hCD22 than the corresponding 9-hydroxy derivative; 7a). Molecular modeling study was carried out to get some insights into the molecular basis of CD22 inhibition. To the best of our knowledge, this is the first systematic structure-affinity relationship study on inhibition of CD22.

• Mimetics of the tri- and tetrasaccharide epitope of GQ1balpha as myelin-associated glycoprotein (MAG) ligands.

  Authors: Ganpan Gao, Martin Smiesko, Oliver Schwardt, Heiko Gäthje, Soerge Kelm, Angelo Vedani, Beat Ernst

  Bioorganic & medicinal chemistry. 01/2008; 15(23):7459-69.

  The synthesis of phenoxyphenyl, phenoxybenzyl, biphenyl, and phenyltriazole substituted sialic acid derivatives as mimics of the tri- and tetrasaccharide epitopes of GQ1balpha is described. TheseThe synthesis of phenoxyphenyl, phenoxybenzyl, biphenyl, and phenyltriazole substituted sialic acid derivatives as mimics of the tri- and tetrasaccharide epitopes of GQ1balpha is described. These synthetically easily available sialosides show comparable or even enhanced affinity to MAG compared with the natural tri- and tetrasaccharide epitopes and form a new class of potential MAG antagonists.

• Sensitivity enhancement in saturation transfer difference (STD) experiments through optimized excitation schemes.

  Authors: Brian Cutting, Sachin V Shelke, Zorica Dragic, Beatrice Wagner, Heiko Gathje, Soerge Kelm, Beat Ernst

  Magnetic resonance in chemistry : MRC. 10/2007; 45(9):720-4.

  Investigation of ligand-protein interactions by the saturation transfer difference (STD) experiment has been well established in the drug discovery process through numerous examples. Thus, bindingInvestigation of ligand-protein interactions by the saturation transfer difference (STD) experiment has been well established in the drug discovery process through numerous examples. Thus, binding epitopes may be mapped by comparing signals of the ligand with and without saturation of the protein. Herein, it is shown that a less selective process allows more protons to assist in the saturation of the protein, thereby considerably enhancing the sensitivity of the STD experiment. Increasing the saturation power entails a greater risk of perturbing the ligand; however, an amplitude modulation of the waveform assists this procedure by distributing the applied energy in sidebands.

• Synthesis of sialic acid derivatives as ligands for the myelin-associated glycoprotein (MAG).

  Authors: Sachin V Shelke, Gan-Pan Gao, Stefanie Mesch, Heiko Gäthje, Soerge Kelm, Oliver Schwardt, Beat Ernst

  Bioorganic & medicinal chemistry. 08/2007; 15(14):4951-65.

  The trisaccharide substructure 13 of the ganglioside GQ1balpha shows a remarkable affinity for the myelin-associated glycoprotein (MAG). In the search for structurally simplified andThe trisaccharide substructure 13 of the ganglioside GQ1balpha shows a remarkable affinity for the myelin-associated glycoprotein (MAG). In the search for structurally simplified and pharmacokinetically improved mimics of 13, sialosides with modifications at the reducing and non-reducing end were synthesized. The biological evaluation of mimics 12a-o was performed in a competitive target-based assay. It was found that the relative inhibitory potency (rIP) of antagonist 12h was enhanced by more than 1000-fold in comparison to the reference trisaccharide 13, despite the former having a much simpler structure. In addition, the sialic acid derivatives, for example, 12h, have clearly improved pharmacokinetic properties due to the presence of aromatic moieties, a lower molecular weight, and a reduced number of polar hydroxy functions compared to the reference compound 13.

• Crystallographic and in silico analysis of the sialoside-binding characteristics of the Siglec sialoadhesin.

  Authors: Nathan R Zaccai, Andrew P May, Robert C Robinson, Leslie D Burtnick, Paul R Crocker, Reinhard Brossmer, Soerge Kelm, E Yvonne Jones

  Journal of molecular biology. 03/2007; 365(5):1469-79.

  The Siglec family of receptors mediates cell-surface interactions through recognition of sialylated glycoconjugates. Previously reported structures of the N-terminal domain of the Siglec sialoadhesinThe Siglec family of receptors mediates cell-surface interactions through recognition of sialylated glycoconjugates. Previously reported structures of the N-terminal domain of the Siglec sialoadhesin (SnD1) in complex with various sialic acid analogs revealed the structural template for sialic acid binding. To characterize further the carbohydrate-binding properties, we have determined the crystal structures of SnD1 in the absence of ligand, and in complex with 2-benzyl-Neu5NPro and 2-benzyl-Neu5NAc. These structures reveal that SnD1 undergoes very few structural changes on ligand binding and detail how two novel classes of sialic acid analogs bind, one of which unexpectedly can induce Siglec dimerization. In conjunction with in silico analysis, this set of structures informs us about the design of putative ligands with enhanced binding affinities and specificities to different Siglecs, and provides data with which to test the effectiveness of different computational drug design protocols.

• Mimetics of the tri- and tetrasaccharide epitope of GQ1b alpha as myelin-associated glycoprotein (MAG) ligands

  Authors: Ganpan Gao, Martin Smiesko, Oliver Schwardt, Heiko Gaethje, Soerge Kelm, Angelo Vedani, Beat Ernst

  Bioorganic & Medicinal Chemistry. 01/2007; 15(23):7459-7469.

• Antagonists of the myelin-associated glycoprotein: a new class of tetrasaccharide mimics.

  Authors: Daniel Schwizer, Heiko Gäthje, Soerge Kelm, Michele Porro, Oliver Schwardt, Beat Ernst

  Bioorganic & medicinal chemistry. 08/2006; 14(14):4944-57.

  The tetrasaccharide substructure 1 of the ganglioside GQ1balpha shows a remarkable affinity for the myelin-associated glycoprotein (MAG). In the search for structurally simplified andThe tetrasaccharide substructure 1 of the ganglioside GQ1balpha shows a remarkable affinity for the myelin-associated glycoprotein (MAG). In the search for structurally simplified and pharmacokinetically improved mimics of 1, biphenyl was identified as a feasible replacement for the core disaccharide Galbeta(1-3)GalNAc according to saturation transfer difference (STD) NMR and molecular modeling investigations. Using Suzuki coupling, a convergent synthesis of the mimics was achieved. To optimize the yields of the coupling reactions, the catalytic effects of microwave irradiation and conventional heating were compared. The biological evaluation of mimics 3 and 4 was performed in a competitive target-based assay. It was found that the relative inhibitory potency (rIP) of antagonist 3 was clearly enhanced in comparison to the reference trisaccharide 2, despite the former having a much simpler structure. In addition to the improved synthetic feasibility, an increase of the partition coefficient between octanol and water (logP), and therefore a beneficial change in the pharmacokinetic properties of 3 and 4 was achieved.

• The structure of siglec-7 in complex with sialosides: leads for rational structure-based inhibitor design.

  Authors: Helen Attrill, Hirokazu Takazawa, Simone Witt, Soerge Kelm, Rainer Isecke, Reinhard Brossmer, Takayuki Ando, Hideharu Ishida, Makoto Kiso, Paul R Crocker, Daan M F van Aalten

  The Biochemical journal. 08/2006; 397(2):271-8.

  Siglecs (sialic acid binding Ig-like lectins) are transmembrane receptors for sialylated glycoconjugates that modulate cellular interactions and signalling events in the haematopoietic, immune andSiglecs (sialic acid binding Ig-like lectins) are transmembrane receptors for sialylated glycoconjugates that modulate cellular interactions and signalling events in the haematopoietic, immune and nervous systems. Siglec-7 is a structural prototype for the recently described family of immune inhibitory CD33-related siglecs and is predominantly expressed on natural killer cells and monocytes, as well as subsets of CD8 T-cells. Siglec-specific inhibitors are desired for the detection of masked and unmasked forms of siglecs, to aid in dissection of signalling pathways and as tools to investigate siglecs as potential therapeutic targets. As a first step towards this end, we present the crystal structure of siglec-7 in complex with a sialylated ligand, the ganglioside analogue DSLc4 [alpha(2,3)/alpha(2,6) disialyl lactotetraosyl 2-(trimethylsilyl)ethyl], which allows for a detailed description of the binding site, required for structure-guided inhibitor design. Mutagenesis and binding assays were used to demonstrate a key structural role for Lys131, a residue that changes conformation upon sialic acid binding. Differences between the binding sites of siglec family members were then exploited using alpha-methyl Neu5Ac (N-acetylneuraminic acid) as a basic scaffold. A co-crystal of siglec-7 in complex with the sialoside inhibitor, oxamido-Neu5Ac [methyl alpha-9-(amino-oxalyl-amino)-9-deoxy-Neu5Ac] and inhibition data for the sialosides gives clear leads for future inhibitor design.

• The ligand-binding domain of CD22 is needed for inhibition of the B cell receptor signal, as demonstrated by a novel human CD22-specific inhibitor compound.

  Authors: Soerge Kelm, Judith Gerlach, Reinhard Brossmer, Claus-Peter Danzer, Lars Nitschke

  The Journal of experimental medicine. 06/2002; 195(9):1207-13.

  CD22 is a B cell-specific transmembrane protein of the Siglec family. It binds specifically to alpha2,6-linked sialic acid (Sia) residues, which are also present on glycoproteins on the B cellCD22 is a B cell-specific transmembrane protein of the Siglec family. It binds specifically to alpha2,6-linked sialic acid (Sia) residues, which are also present on glycoproteins on the B cell surface. CD22 acts as a negative regulator in B cell receptor-mediated signaling by recruitment of Src homology 2 domain-containing tyrosine phosphatase (SHP)-1 to its intracellular tail. To analyze how ligand-binding of CD22 influences its intracellular signaling domain, we designed synthetic sialosides as inhibitors for the lectin domain of CD22. One of these compounds inhibited binding of human CD22-Fc to target cells over 200-fold better than Sia and was highly selective for human CD22. When Daudi cells or primary B cells were stimulated with anti-immunoglobulin (Ig)M in presence of this sialoside inhibitor, a higher Ca(2+) response was observed, similar to CD22-deficient B cells. Accordingly, a lower tyrosine-phosphorylation of CD22 and SHP-1 recruitment was demonstrated in presence of the sialoside. Thus, by interfering with ligand binding of CD22 on the B cell surface, we have shown for the first time that the lectin domain of CD22 has a direct, positive influence on its intracellular inhibitory domain. Also, we have developed a novel low molecular weight compound which can enhance the response of human B cells.

• Crystallographic and in Silico Analysis of the Sialoside-binding Characteristics of the Siglec Sialoadhesin

  Authors: Nathan R. Zaccai, Andrew P. May, Robert C. Robinson, Leslie D. Burtnick, Paul R. Crocker, Reinhard Brossmer, Soerge Kelm, E. Yvonne Jones

  Journal of Molecular Biology.

  The Siglec family of receptors mediates cell-surface interactions through recognition of sialylated glycoconjugates. Previously reported structures of the N-terminal domain of the Siglec sialoadhesinThe Siglec family of receptors mediates cell-surface interactions through recognition of sialylated glycoconjugates. Previously reported structures of the N-terminal domain of the Siglec sialoadhesin (SnD1) in complex with various sialic acid analogs revealed the structural template for sialic acid binding. To characterize further the carbohydrate-binding properties, we have determined the crystal structures of SnD1 in the absence of ligand, and in complex with 2-benzyl-Neu5NPro and 2-benzyl-Neu5NAc. These structures reveal that SnD1 undergoes very few structural changes on ligand binding and detail how two novel classes of sialic acid analogs bind, one of which unexpectedly can induce Siglec dimerization. In conjunction with in silico analysis, this set of structures informs us about the design of putative ligands with enhanced binding affinities and specificities to different Siglecs, and provides data with which to test the effectiveness of different computational drug design protocols.