Hendrik Koliwer-Brandl

Publications of Hendrik Koliwer-Brandl

• From a library of MAG antagonists to nanomolar CD22 ligands.

  Authors: Stefanie Mesch, Katrin Lemme, Matthias Wittwer, Hendrik Koliwer-Brandl, Oliver Schwardt, Sørge Kelm, Beat Ernst

  ChemMedChem. 01/2012; 7(1):134-43.

  Siglec-2, also known as CD22, is involved in the regulation and survival of B-cells and has been successfully targeted in cell depletion therapies with antibody-based approaches. Sialic acidSiglec-2, also known as CD22, is involved in the regulation and survival of B-cells and has been successfully targeted in cell depletion therapies with antibody-based approaches. Sialic acid derivatives, already known to bind with high affinity to myelin-associated glycoprotein (MAG, Siglec-4), were screened for their binding affinity for CD22 by surface plasmon resonance. The best compound identified was further modified with various hydrophobic substituents at the 2-, 5-, and 9-positions of the sialic acid scaffold, leading to nanomolar derivatives, of which ligand 17 b shows the most promising pharmacodynamic and pharmacokinetic profiles. Isothermal titration calorimetry measurements demonstrate that the binding is enthalpy driven. Interestingly, the thermodynamic fingerprints reveal an excellent correlation between gains in enthalpy and compensation by increased entropy costs. Moreover, 17 b exhibits a residence time in the range of a few seconds, clearly prolonged relative to residence times typically observed for carbohydrate-lectin interactions. Finally, initial tests regarding drug-like properties of 17 b demonstrate the required high plasma protein binding yet a lack of oral availability, although its distribution coefficient (log D) is in the required range.

• Impact of strong and weak lipid-protein interactions on the structure of a lipid bilayer on a gold electrode surface.

  Authors: Martina Nullmeier, Hendrik Koliwer-Brandl, Sørge Kelm, Patrick Zägel, Karl-Wilhelm Koch, Izabella Brand

  Chemphyschem : a European journal of chemical physics and physical chemistry. 03/2011; 12(6):1066-79.

  A lipid bilayer deposited on an electrode surface can serve as a benchmark system to investigate lipid-protein interactions in the presence of physiological electric fields. Recoverin andA lipid bilayer deposited on an electrode surface can serve as a benchmark system to investigate lipid-protein interactions in the presence of physiological electric fields. Recoverin and myelin-associated glycoprotein (MAG) are used to study the impact of strong and weak protein-lipid interactions on the structure of model lipid bilayers, respectively. The structural changes in lipid bilayers are followed using electrochemical polarization modulation infrared reflection-absorption spectroscopy (PM IRRAS). Recoverin contains a myristoyl group that anchors in the hydrophobic part of a cell membrane. Insertion of the protein into the 1,2-dimyristoyl-sn-glycero-3-phosphatidylcholine (DMPC)-cholesterol lipid bilayer leads to an increase in the capacitance of the lipid film adsorbed on a gold electrode surface. The stability and kinetics of the electric-field-driven adsorption-desorption process are not affected by the interaction with protein. Upon interaction with recoverin, the hydrophobic hydrocarbon chains become less ordered. The polar head groups are separated from each other, which allows for recoverin association in the membrane. MAG is known to interact with glycolipids present on the surface of a cell membrane. Upon probing the interaction of the DMPC-cholesterol-glycolipid bilayer with MAG a slight decrease in the capacity of the adsorbed lipid film is observed. The stability of the lipid bilayer increases towards negative potentials. At the molecular scale this interaction results in minor changes in the structure of the lipid bilayer. MAG causes small ordering in the hydrocarbon chains region and an increase in the hydration of the polar head groups. Combining an electrochemical approach with a structure-sensitive technique, such as PM IRRAS, is a powerful tool to follow small but significant changes in the structure of a supramolecular assembly.

• 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.

• Design, synthesis, biological evaluation, and modeling of a non-carbohydrate antagonist of the myelin-associated glycoprotein.

  Authors: Oliver Schwardt, Hendrik Koliwer-Brandl, Raphael Zimmerli, Stefanie Mesch, Gianluca Rossato, Morena Spreafico, Angelo Vedani, Sørge Kelm, Beat Ernst

  Bioorganic & medicinal chemistry. 10/2010; 18(20):7239-51.

  Broad modifications of various positions of the minimal natural epitope recognized by the myelin-associated glycoprotein (MAG), a blocker of regeneration of neurite injuries, produced sialosides withBroad modifications of various positions of the minimal natural epitope recognized by the myelin-associated glycoprotein (MAG), a blocker of regeneration of neurite injuries, produced sialosides with nanomolar affinities. However, important pharmacokinetic issues, for example, the metabolic stability of these sialosides, remain to be addressed. For this reason, the novel non-carbohydrate mimic 3 was designed and synthesized from (-)-quinic acid. For the design of 3, previously identified beneficial modifications of side chains of Neu5Ac were combined with the replacement of the ring oxygen by a methylene group and the substitution of the C(4)-OH by an acetamide. Although docking experiments to a homology model of MAG revealed that mimic 3 forms all but one of the essential hydrogen bonds identified for the earlier reported lead 2, its affinity was substantially reduced. Extensive molecular-dynamics simulation disclosed that the missing hydrogen bond of the former C(8)-OH leads to a change of the orientation of the side chain. As a consequence, an important hydrophobic contact is compromised leading to a loss of affinity.

• 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.

• Interaction of siglec protein with glycolipids in a lipid bilayer deposited on a gold electrode surface

  Authors: Martina Nullmeier, Hendrik Koliwer-Brandl, Sørge Kelm, Izabella Brand

  Journal of Electroanalytical Chemistry.

  Unsymmetric three component lipid bilayers containing 1,2-dimyristoyl-sn-glycero-3-phosphatidylcholine (DMPC), cholesterol and a ganglioside were prepared using theUnsymmetric three component lipid bilayers containing 1,2-dimyristoyl-sn-glycero-3-phosphatidylcholine (DMPC), cholesterol and a ganglioside were prepared using the Langmuir–Blodgett–Langmuir–Schaefer (LB–LS) technique on the surface of a polycrystalline gold electrode. The lipid layer contains the ganglioside only in the outer layer, mimicking a natural cell membrane. Gangliosides are glycolipids containing at least one sialic acid residue and are proposed to be a binding partner for siglec proteins. Interaction between Siglec-4, the myelin-associated glycoprotein (MAG) and two gangliosides in lipid bilayers was investigated. MAG protein binds only to the sialic acid residue located at the terminal position in the oligosaccharide head group of a lipid molecule. In this study two gangliosides, the GD1a having one terminal sialic acid residue and the GM1 not possessing a terminal sialic acid residue in the polar head group were used. Under physiological conditions a lipid membrane is constantly exposed to high electric fields. Three component lipid bilayers transferred by the LB–LS method are characterized by capacitance minimum equal to 2.3 and 5.0 μF cm−2 in the film containing the GM1 and GD1a, respectively. The lipid bilayer desorbs form the electrode surface at E < −0.8 V vs. Ag|AgCl. The potential driven adsorption–desorption process is irreversible and leads to an increase in the capacitance of the adsorbed lipid films. The lipid films undergo some irreversible changes which may lead to a flip–flop of bilayer fragments, formation of micelles on the electrode surface or decrease in surface coverage. Exposure of the bilayer to the protein solution stabilizes lipid films adsorbed directly on the electrode surface. The potential induced adsorption of the bilayer containing the GD1a in the presence of the protein hinders structural changes taking place in the lipid film exposed to changing electric fields. At the molecular level the binding of the protein to the GD1a introduces structural changes not only in the glycolipid molecule, but in the whole membrane. In the polar head group of the GD1a amide groups in sialic acid residues lose some water of hydration upon interaction with the protein. The hydrocarbon chains of the GD1a exhibit ordering with respect to the surface normal. Reorientations in the ganglioside molecule may lead to changes in the phosphatidylcholine, main lipid component of the bilayer. In the DMPC molecule the dehydration of the ester group with simultaneous change in tilt of the acyl chains were observed.