Sandhausen, Germany
Sandhausen, Germany

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Prescher H.,G3 BioTec | Frank M.,German Cancer Research Center | Gutgemann S.,University of Heidelberg | Kuhfeldt E.,G3 BioTec | And 5 more authors.
Journal of Medicinal Chemistry | Year: 2017

Natural killer cells are able to directly lyse tumor cells, thereby participating in the immune surveillance against cancer. Unfortunately, many cancer cells use immune evasion strategies to avoid their eradication by the immune system. A prominent escape strategy of malignant cells is to camouflage themselves with Siglec-7 ligands, thereby recruiting the inhibitory receptor Siglec-7 expressed on the NK cell surface which subsequently inhibits NK-cell-mediated lysis. Here we describe the synthesis and evaluation of the first, high-affinity low molecular weight Siglec-7 ligands to interfere with cancer cell immune evasion. The compounds are Sialic acid derivatives and bind with low micromolar Kd values to Siglec-7. They display up to a 5000-fold enhanced affinity over the unmodified sialic acid scaffold αMe Neu5Ac, the smallest known natural Siglec-7 ligand. Our results provide a novel immuno-oncology strategy employing natural immunity in the fight against cancers, in particular blocking Siglec-7 with low molecular weight compounds. © 2017 American Chemical Society.


Prescher H.,G3 BioTec | Schweizer A.,Friedrich - Alexander - University, Erlangen - Nuremberg | Kuhfeldt E.,G3 BioTec | Nitschke L.,Friedrich - Alexander - University, Erlangen - Nuremberg | Brossmer R.,University of Heidelberg
ACS Chemical Biology | Year: 2014

Sialic acids are abundant in higher domains of life and lectins recognizing sialosaccharides are heavily involved in the regulation of the human immune system. Modified sialosides are useful tools to explore the functions of those lectins, especially members of the Siglec (sialic acid binding immunoglobulin like lectin) family. Here we report design, synthesis, and affinity evaluation of novel sialoside classes with combined modification at positions 2, 4, and 9 or 2, 3, 4, and 9 of the sialic acid scaffold as human CD22 (human Siglec-2) ligands. They display up to 7.5 × 105-fold increased affinity over αMe Neu5Ac (the minimal Siglec ligand). CD22 is a negative regulating coreceptor of the B-cell receptor (BCR). In vitro experiments with a human B-lymphocyte cell line showed functional blocking of CD22 upon B-cell receptor (BCR) stimulation in the presence of nanomolar concentrations of the novel ligands. The observed increased Ca2+ response corresponds to enhanced cell activation, providing an opportunity to therapeutically modulate B-lymphocyte responses, e.g., in immune deficiencies and infections. © 2014 American Chemical Society.


Pietrancosta N.,University of Paris Descartes | Anne C.,University of Paris Descartes | Prescher H.,G3 BioTec | Ruivo R.,University of Paris Descartes | And 7 more authors.
Journal of Biological Chemistry | Year: 2012

Secondary active transporters from the SLC17 protein family are required for excitatory and purinergic synaptic transmission, sialic acid metabolism, and renal function, and several members are associated with inherited neurological or metabolic diseases. However, molecular tools to investigate their function or correct their genetic defects are limited or absent. Using structure-activity, homology modeling, molecular docking, and mutagenesis studies, we have located the substratebinding site of sialin (SLC17A5), a lysosomal sialic acid exporter also recently implicated in exocytotic release of aspartate. Human sialin is defective in two inherited sialic acid storage diseases and is responsible for metabolic incorporation of the dietary nonhuman sialic acid N-glycolylneuraminic acid. We built cytosol-open and lumen-open three-dimensional models of sialin based on weak, but significant, sequence similarity with the glycerol-3-phosphate and fucose permeases from Escherichia coli, respectively. Molecular docking of 31 synthetic sialic acid analogues to both models was consistent with inhibition studies. Narrowing the sialic acid-binding site in the cytosol-open state by two phenylalanine to tyrosine mutations abrogated recognition of the most active analogue without impairing neuraminic acid transport. Moreover, a pilot virtual high-throughput screening of the cytosol-open model could identify a pseudopeptide competitive inhibitor showing >100-fold higher affinity than the natural substrate. This validated model of human sialin and sialin-guided models of other SLC17 transporters should pave the way for the identification of inhibitors, glycoengineering tools, pharmacological chaperones, and fluorescent false neurotransmitters targeted to these proteins. © 2012 by The American Society for Biochemistry and Molecular Biology, Inc.


Prescher H.,G3 BioTec | Gutgemann S.,University of Heidelberg | Gutgemann S.,TU Dortmund | Frank M.,German Cancer Research Center | And 6 more authors.
Bioorganic and Medicinal Chemistry | Year: 2015

Siglecs (sialic acid recognizing immunoglobulin like lectins) are a family of lectins with specificity for sialic acid containing carbohydrates. Synthetic sialic acid derivatives with high affinity proved useful to unravel the biological role of the ligand binding domain, although many of their functions in immunity remain unknown. Here we present design, synthesis, affinity evaluation and molecular modeling of novel 9-N-oxamoyl modified sialosides as Siglec-7 ligands. © 2015 Elsevier Ltd.


Prescher H.,G3 BioTec | Gutgemann S.,University of Heidelberg | Gutgemann S.,TU Dortmund | Frank M.,German Cancer Research Center | And 5 more authors.
Bioorganic and Medicinal Chemistry | Year: 2015

Siglecs (sialic acid recognizing immunoglobulin like lectins) are a family of lectins with specificity for sialic acid containing carbohydrates. Synthetic sialic acid derivatives with high affinity proved useful to unravel the biological role of the ligand binding domain, although many of their functions in immunity remain unknown. Here we present design, synthesis, affinity evaluation and molecular modeling of novel 9-N-oxamoyl modified sialosides as Siglec-7 ligands. © 2015 Elsevier Ltd. All rights reserved.


Schweizer A.,Friedrich - Alexander - University, Erlangen - Nuremberg | Wohner M.,Friedrich - Alexander - University, Erlangen - Nuremberg | Prescher H.,G3 Biotec | Brossmer R.,University of Heidelberg | Nitschke L.,Friedrich - Alexander - University, Erlangen - Nuremberg
European Journal of Immunology | Year: 2012

CD22 is an inhibitory co-receptor of the B-cell receptor (BCR) on B cells. Since CD22 is ubiquitously expressed in the B-cell lineage and CD22 endocytosis can be triggered efficiently, antibodies and antibody-based immunotoxins against CD22 are used to target B cells both in B-cell lymphomas and leukemias, as well as in autoimmune diseases. CD22 recognizes α2,6-linked sialic acids as endogenous ligands. We have developed new synthetic sialosides as ligands for human CD22. These sialosides bind CD22 on human B cells with high affinity and can efficiently enhance IgM-triggered Ca2+ signaling. We coupled these sialosides to Pseudomonas exotoxin A to generate a novel CD22 ligand-based immunotoxin. This sialoside-exotoxin-A construct can specifically kill CD22-positive B-cell lymphoma cells. It binds specifically to CD22-positive B-cell lymphoma cells and is dominant over endogenous cis-ligands on the B-cell surface. The sialoside-exotoxin-A construct is efficiently internalized by endocytosis into B-cell lymphoma cell lines. Thus we show the development of a new therapeutic compound for targeting CD22 on human B cells, both for B-cell lymphoma, as well as for B-cell-mediated autoimmune diseases. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


PubMed | G3 BioTec, University of Heidelberg and German Cancer Research Center
Type: Journal Article | Journal: Bioorganic & medicinal chemistry | Year: 2015

Siglecs (sialic acid recognizing immunoglobulin like lectins) are a family of lectins with specificity for sialic acid containing carbohydrates. Synthetic sialic acid derivatives with high affinity proved useful to unravel the biological role of the ligand binding domain, although many of their functions in immunity remain unknown. Here we present design, synthesis, affinity evaluation and molecular modeling of novel 9-N-oxamoyl modified sialosides as Siglec-7 ligands.

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