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PNA‐Encoded Synthesis (PES) of a 10 000‐Member Hetero‐Glycoconjugate Library and Microarray Analysis of Diverse Lectins 下载免费PDF全文
Dr. Alexandre Novoa Takuya Machida Dr. Sofia Barluenga Dr. Anne Imberty Prof. Nicolas Winssinger 《Chembiochem : a European journal of chemical biology》2014,15(14):2058-2065
Identification of selective and synthetically tractable ligands to glycan‐binding proteins is important in glycoscience. Carbohydrate arrays have had a tremendous impact on profiling glycan‐binding proteins and as analytical tools. We report a highly miniaturized synthetic format to access nucleic‐acid‐encoded hetero‐glycoconjugate libraries with an unprecedented diversity in the combinations of glycans, linkers, and capping groups. Novel information about plant and bacterial lectin specificity was obtained by microarray profiling, and we show that a ligand identified on the array can be converted to a high‐affinity soluble ligand by straightforward chemistry. 相似文献
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Sébastien G. Gouin Dr. Adinda Wellens Julie Bouckaert Dr. José Kovensky Prof. 《ChemMedChem》2009,4(5):749-755
Sweet medicine : Multimeric glycoconjugates with valencies ranging from one to four were synthesized by click chemistry. Unprecedented adhesion inhibitions of piliated E. coli to human bladder cells were recorded with the multimers; a tetravalent derivative showed inhibitory concentrations 6000‐ and 64‐fold lower than mannose and heptyl α‐D ‐mannoside, respectively.
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Chafekar SM Malda H Merkx M Meijer EW Viertl D Lashuel HA Baas F Scheper W 《Chembiochem : a European journal of chemical biology》2007,8(15):1857-1864
The key pathogenic event in the onset of Alzheimer's disease (AD) is the aggregation of beta-amyloid (Abeta) peptides into toxic aggregates. Molecules that interfere with this process might act as therapeutic agents for the treatment of AD. The amino acid residues 16-20 (KLVFF) are known to be essential for the aggregation of Abeta. In this study, we have used a first-generation dendrimer as a scaffold for the multivalent display of the KLVFF peptide. The effect of four KLVFF peptides attached to the dendrimer (K(4)) on Abeta aggregation was compared to the effect of monomeric KLVFF (K(1)). Our data show that K(4) very effectively inhibits the aggregation of low-molecular-weight and protofibrillar Abeta(1-42) into fibrils, in a concentration-dependent manner, and much more potently than K(1). Moreover, we show that K(4) can lead to the disassembly of existing aggregates. Our data lead us to propose that conjugates that bear multiple copies of KLVFF might be useful as therapeutic agents for the treatment of Alzheimer's disease. 相似文献
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A Peptide‐Functionalized Polymer as a Minimal Scaffold Protein To Enhance Cluster Formation in Early T Cell Signal Transduction 下载免费PDF全文
J. Joris Witsenburg Michael D. Sinzinger Dr. Oda Stoevesandt Dr. Ivo R. Ruttekolk Dr. Günter Roth Dr. Merel J. W. Adjobo‐Hermans Prof. Dr. Roland Brock 《Chembiochem : a European journal of chemical biology》2015,16(4):602-610
In cellular signal transduction, scaffold proteins provide binding sites to organize signaling proteins into supramolecular complexes and act as nodes in the signaling network. Furthermore, multivalent interactions between the scaffold and other signaling proteins contribute to the formation of protein microclusters. Such microclusters are prominent in early T cell signaling. Here, we explored the minimal structural requirement for a scaffold protein by coupling multiple copies of a proline‐rich peptide corresponding to an interaction motif for the SH3 domain of the adaptor protein GADS to an N‐(2‐hydroxypropyl)methacrylamide polymer backbone. When added to GADS‐containing cell lysates, these scaffolds (but not individual peptides) promoted the binding of GADS to peptide microarrays. This can be explained by the cross‐linking of GADS into larger complexes. Furthermore, following import into Jurkat T cell leukemia cells, this synthetic scaffold enhanced the formation of microclusters of signaling proteins. 相似文献
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Ehsan Mohammadifar Vahid Ahmadi Mohammad Fardin Gholami Alexander Oehrl Oleksandr Kolyvushko Chuanxiong Nie Ievgen S. Donskyi Svenja Herziger Jörg Radnik Kai Ludwig Christoph Böttcher Jürgen P. Rabe Klaus Osterrieder Walid Azab Rainer Haag Mohsen Adeli 《Advanced functional materials》2021,31(22):2009003
2D nanomaterials have garnered widespread attention in biomedicine and bioengineering due to their unique physicochemical properties. However, poor functionality, low solubility, intrinsic toxicity, and nonspecific interactions at biointerfaces have hampered their application in vivo. Here, biocompatible polyglycerol units are crosslinked in two dimensions using a graphene-assisted strategy leading to highly functional and water-soluble polyglycerols nanosheets with 263 ± 53 nm and 2.7 ± 0.2 nm average lateral size and thickness, respectively. A single-layer hyperbranched polyglycerol containing azide functional groups is covalently conjugated to the surface of a functional graphene template through pH-sensitive linkers. Then, lateral crosslinking of polyglycerol units is carried out by loading tripropargylamine on the surface of graphene followed by lifting off this reagent for an on-face click reaction. Subsequently, the polyglycerol nanosheets are detached from the surface of graphene by slight acidification and centrifugation and is sulfated to mimic heparin sulfate proteoglycans. To highlight the impact of the two-dimensionality of the synthesized polyglycerol sulfate nanosheets at nanobiointerfaces, their efficiency with respect to herpes simplex virus type 1 and severe acute respiratory syndrome corona virus 2 inhibition is compared to their 3D nanogel analogs. Four times stronger in virus inhibition suggests that 2D polyglycerols are superior to their current 3D counterparts. 相似文献
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Dr. Magdalena Eriksson Dr. Sonia Serna Dr. Maha Maglinao Dr. Mark K. Schlegel Prof. Dr. Peter H. Seeberger Dr. Niels‐Christian Reichardt Dr. Bernd Lepenies 《Chembiochem : a European journal of chemical biology》2014,15(6):844-851
Myeloid C‐type lectin receptors (CLRs) expressed by antigen‐presenting cells are pattern‐recognition receptors involved in the recognition of pathogens as well as of self‐antigens. The interaction of carbohydrate ligands with a CLR can trigger immune responses. Although several CLR ligands are known, there is limited insight into CLR targeting by carbohydrate ligands. The weak affinity of lectin–carbohydrate interactions often renders multivalent carbohydrate presentation necessary. Here, we have analyzed the impact of multivalent presentation of the trisaccharide Lewis X (LeX) epitope on its interaction with the CLR macrophage galactose‐type lectin‐1 (MGL‐1). Glycan arrays, including N‐glycan structures with terminal LeX, were prepared by enzymatic extension of immobilized synthetic core structures with two recombinant glycosyltransferases. Incubation of arrays with an MGL‐1‐hFc fusion protein showed up to tenfold increased binding to multiantennary N‐glycans displaying LeX structures, compared to monovalent LeX trisaccharide. Multivalent presentation of LeX on the model antigen ovalbumin (OVA) led to increased cytokine production in a dendritic cell /T cell coculture system. Furthermore, immunization of mice with LeX‐OVA conjugates modulated cytokine production and the humoral response, compared to OVA alone. This study provides insights into how multivalent carbohydrate–lectin interactions can be exploited to modulate immune responses. 相似文献
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A Systematic Investigation of Iminosugar Click Clusters as Pharmacological Chaperones for the Treatment of Gaucher Disease 下载免费PDF全文
Dr. Antoine Joosten Dr. Camille Decroocq Julien de Sousa Jérémy P. Schneider Emile Etamé Dr. Anne Bodlenner Dr. Terry D. Butters Prof. Philippe Compain 《Chembiochem : a European journal of chemical biology》2014,15(2):309-319
A series of 18 mono‐ to 14‐valent iminosugars with different ligands, scaffolds, and alkyl spacer lengths have been synthesized and evaluated as inhibitors and pharmacological chaperones of β‐glucocerebrosidase (GCase). Small but significant multivalent effects in GCase inhibition have been observed for two iminosugar clusters. Our study provides strong confirmation that compounds that display the best affinity for GCase are not necessarily the best chaperones. The best chaperoning effect observed for a deprotected iminosugar cluster has been obtained with a tetravalent 1‐deoxynojirimycin (DNJ) analogue (3.3‐fold increase at 10 μM ). In addition, our study provides the first evidence of the high potential of prodrugs for the development of potent pharmacological chaperones. Acetylation of a trivalent DNJ derivative, to give the corresponding acetate prodrug, leads to a pharmacological chaperone that produces higher enzyme activity increases (3.0‐fold instead of 2.4‐fold) at a cellular concentration (1 μM ) reduced by one order of magnitude. 相似文献
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Sara Bertuzzi Ana Gimeno Ane Martinez-Castillo Marta G. Lete Sandra Delgado Cristina Airoldi Marina Rodrigues Tavares Markta Blhov Petr Chytil Vladimír Ken Nicola G. A. Abrescia Ana Ard Pavla Bojarov Jesús Jimnez-Barbero 《International journal of molecular sciences》2021,22(11)
The interaction of multi-LacNAc (Galβ1-4GlcNAc)-containing N-(2-hydroxypropyl) methacrylamide (HPMA) copolymers with human galectin-1 (Gal-1) and the carbohydrate recognition domain (CRD) of human galectin-3 (Gal-3) was analyzed using NMR methods in addition to cryo-electron-microscopy and dynamic light scattering (DLS) experiments. The interaction with individual LacNAc-containing components of the polymer was studied for comparison purposes. For Gal-3 CRD, the NMR data suggest a canonical interaction of the individual small-molecule bi- and trivalent ligands with the lectin binding site and better affinity for the trivalent arrangement due to statistical effects. For the glycopolymers, the interaction was stronger, although no evidence for forming a large supramolecule was obtained. In contrast, for Gal-1, the results indicate the formation of large cross-linked supramolecules in the presence of multivalent LacNAc entities for both the individual building blocks and the polymers. Interestingly, the bivalent and trivalent presentation of LacNAc in the polymer did not produce such an increase, indicating that the multivalency provided by the polymer is sufficient for triggering an efficient binding between the glycopolymer and Gal-1. This hypothesis was further demonstrated by electron microscopy and DLS methods. 相似文献