74 research outputs found
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Modulating Myeloid Immune Cell Migration Using Multivalently Presented Monosaccharide Ligands for Advanced Immunotherapy
Due to their importance for the outcome of the inflammatory response, the motile myeloid cells are a focus of novel treatment options. The interplay of selectins and their ligands with leukocytes and endothelial cells, which mediate endothelial attachment and transmigration of immune cells, can be modulated by selectinâbinding structures. Here, a library of selectinâtargeting ligands coupled to either gold, silver, iron oxide nanospheres, or quantum dots of 5â10Â nm in size is used to systematically study their impact on immune cell motility. The multivalent presentation of the carbohydrate mimetics results in very low subânanomolar binding to L âselectin. Using human primary monocytes, granulocytes, lymphocytes, and macrophages, it is shown that the ligands exhibit only minor effects on uptake, whereas the motility of leukocytes is critically affected as observed in migration assays evaluated by flow cytometry. The carbohydrate mimetic ring structure, sulfation, in particular, and the degree of ligand presentation, are constituents which cohere in this process. Specific carbohydrate ligands can thus selectively regulate leukocyte subsets. These data form the basis for advanced immunotherapy which inhibits the amplification of inflammation by restricting leukocyte influx to injured tissue sites. Furthermore, the targeting ligands may complement existing treatment options for inflammatory diseases
Polysulfate hemmen durch elektrostatische Wechselwirkungen die SARS-CoV-2-Infektion
Wir zeigen, dass negativ geladene Polysulfate durch elektrostatische Wechselwirkungen an das Spike-Protein von SARS-CoV-2 binden. Durch einen Plaquereduktionstest verglichen wir die hemmende Wirkung von Heparin, Pentosanpolysulfat, linearem Polyglycerolsulfat (LPGS) und hyperverzweigtem Polyglycerolsulfat (HPGS) gegengber SARSCoV-2. Dabei ist das synthetische LPGS der vielversprechendste Inhibitor mit IC50=67 ÎŒgmL-1 (ca. 1,6 ÎŒm) und zeigt eine 60-fach hçhere virushemmende AktivitĂ€t als Heparin (IC50=4084 ÎŒgmL-1) bei zugleich deutlich geringerer gerinnungshemmender AktivitĂ€t. AuĂerdem konnten wir durch MolekĂŒldynamiksimulationen bestĂ€tigen, dass LPGS stĂ€rker an das Spike-Protein bindet als Heparin selbst und dass LPGS sogar noch stĂ€rker an die Spike-Proteine der neuen N501Yund E484K-Varianten bindet. Unsere Studien belegen, dass die Aufnahme von SARS-CoV-2 in Wirtzellen ĂŒber elektrostatische Wechselwirkungen blockiert werden kann. Deshalb kann LPGS als vielversprechender Prototyp fĂŒr das Design weiterer neuartiger viraler Inhibitoren von SARS-CoV-2 herangezogen werden
Polysulfates block SARS-CoV-2 uptake through electrostatic interactions
Here we report that negatively charged polysulfates can bind to the spike protein of SARS-CoV-2 via electrostatic interactions. Using a plaque reduction assay, we compare inhibition of SARS-CoV-2 by heparin, pentosan sulfate, linear polyglycerol sulfate (LPGS) and hyperbranched polyglycerol sulfate (HPGS). Highly sulfated LPGS is the optimal inhibitor, with a half-maximal inhibitory concentration (IC50) of 67 ÎŒg/mL (approx.1.6 ÎŒM). This synthetic polysulfates exhibit more than 60-fold higher virus inhibitory activity than heparin (IC50: 4084ÎŒg/mL), along with much lower anticoagulant activity. Furthermore, in molecular dynamics simulations, we verified that LPGS can bind stronger to the spike protein than heparin, and that LPGS can interact even morewith the spike protein of the new N501Y and E484K variants. Our study demonstrates that the entry of SARS-CoV-2 into host cells can be blocked via electrostatic interaction, therefore LPGS can serve as a blueprint for the design of novel viral inhibitors of SARS-CoV-2
Polysulfates block SARSâCoVâ2 uptake through electrostatic interactions
Here we report that negatively charged polysulfates can bind to the spike protein of SARS-CoV-2 via electrostatic interactions. Using a plaque reduction assay, we compare inhibition of SARS-CoV-2 by heparin, pentosan sulfate, linear polyglycerol sulfate (LPGS) and hyperbranched polyglycerol sulfate (HPGS). Highly sulfated LPGS is the optimal inhibitor, with a half-maximal inhibitory concentration (IC50) of 67 ÎŒg/mL (approx. 1.6 ÎŒM). This synthetic polysulfates exhibit more than 60-fold higher virus inhibitory activity than heparin (IC50: 4084 ÎŒg/mL), along with much lower anticoagulant activity. Furthermore, in molecular dynamics simulations, we verified that LPGS can bind stronger to the spike protein than heparin, and that LPGS can interact even more with the spike protein of the new N501Y and E484K variants. Our study demonstrates that the entry of SARS-CoV-2 into host cells can be blocked via electrostatic interaction, therefore LPGS can serve as a blueprint for the design of novel viral inhibitors of SARS-CoV-2
Use of anticoagulants and antiplatelet agents in stable outpatients with coronary artery disease and atrial fibrillation. International CLARIFY registry
Modulating Myeloid Immune Cell Migration Using Multivalently Presented Monosaccharide Ligands for Advanced Immunotherapy
Due to their importance for the outcome of the inflammatory response, the motile myeloid cells are a focus of novel treatment options. The interplay of selectins and their ligands with leukocytes and endothelial cells, which mediate endothelial attachment and transmigration of immune cells, can be modulated by selectinâbinding structures. Here, a library of selectinâtargeting ligands coupled to either gold, silver, iron oxide nanospheres, or quantum dots of 5â10Â nm in size is used to systematically study their impact on immune cell motility. The multivalent presentation of the carbohydrate mimetics results in very low subânanomolar binding to L âselectin. Using human primary monocytes, granulocytes, lymphocytes, and macrophages, it is shown that the ligands exhibit only minor effects on uptake, whereas the motility of leukocytes is critically affected as observed in migration assays evaluated by flow cytometry. The carbohydrate mimetic ring structure, sulfation, in particular, and the degree of ligand presentation, are constituents which cohere in this process. Specific carbohydrate ligands can thus selectively regulate leukocyte subsets. These data form the basis for advanced immunotherapy which inhibits the amplification of inflammation by restricting leukocyte influx to injured tissue sites. Furthermore, the targeting ligands may complement existing treatment options for inflammatory diseases
Polyglycerolsulfate functionalized gold nanorods as optoacoustic signal nanoamplifiers for <em>in vivo</em> bioimaging of rheumatoid arthritis.
We have synthesized a targeted imaging agent for rheumatoid arthritis based on polysulfated gold nanorods. The CTAB layer on gold nanorods was first replaced with PEG-thiol and then with dendritic polyglycerolsulfate at elevated temperature, which resulted in significantly reduced cytotoxicity compared to polyanionic gold nanorods functionalized by non-covalent approaches. In addition to classical characterization methods, we have established a facile UV-VIS based BaCl2 agglomeration assay to confirm a quantitative removal of unbound ligand. With the help of a competitive surface plasmon resonance-based L-selectin binding assay and a leukocyte adhesion-based flow cell assay, we have demonstrated the high inflammation targeting potential of the synthesized gold nanorods in vitro. In combination with the surface plasmon resonance band of AuNRs at 780 nm, these findings permitted the imaging of inflammation in an in vivo mouse model for rheumatoid arthritis with high contrast using multispectral optoacoustic tomography. The study offers a robust method for otherwise difficult to obtain covalently functionalized polyanionic gold nanorods, which are suitable for biological applications as well as a low-cost, actively targeted, and high contrast imaging agent for the diagnosis of rheumatoid arthritis. This paves the way for further research in other inflammation associated pathologies, in particular, when photothermal therapy can be applied
Synthesis, Photophysical, and Biological Evaluation of Sulfated Polyglycerol Dendronized Perylenebisimides (PBIs)îžA Promising Platform for Anti-Inflammatory Theranostic Agents?
A set of four water-soluble perylene
bisimides (PBI) based on sulfated
polyglycerol (PGS) dendrons were developed, their photophysical properties
determined via UV/vis and fluorescence spectroscopy, and their performance
as possible anti-inflammatory agents evaluated via biological in vitro
studies. It could be shown that in contrast to charge neutral PGâPBIs
the introduction of the additional electrostatic repulsion forces
leads to a decrease in the dendron generation necessary for aggregation
suppression, allowing the preparation of PBIs with fluorescence quantum
yields of >95% with a considerable decreased synthetic effort.
Furthermore,
the values determined for L-selectin binding down to the nanomolar
range, their limited impact on blood coagulation, and their minor
activation of the complement system renders these systems ideal for
anti-inflammatory purposes
South West London Cancer Network (SWLCN) audit of patients with chemotherapy-induced febrile neutropenia (CIFN)
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