Non‐Covalent Polyvalent Ligands by Self‐Assembly of Small Glycodendrimers: A Novel Concept for the Inhibition of Polyvalent Carbohydrate–Protein Interactions In Vitro and In Vivo

Thoma, Gebhard; Streiff, Markus; Katopodis, Andreas; Duthaler, Rudolf O.; Voelcker, Nicolas H.; Ehrhardt, Claus; Masson, Christophe

doi:10.1002/chem.200500901

Cited by 36 publications

(34 citation statements)

References 48 publications

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“…Glycoclusters [10] have been obtained by appending saccharide residues to b-cyclodextrin [11] and calixarene cores. [10] Other approaches have involved, for example, combinatorial glycosamino acids [12] and oligosaccharide [13] derivatives, dynamic monolayers, [14] a polyrotaxane, [15] self-assembling glycodendrimers, [16] and conjugating carbohydrate residues to a polymerizable scaffold, to prepare glycopolymers. [17] Extending our work on dynamers [4, 5a, 6, 7] to the biopolymer area, [8b] we were interested in designing a dynamic analogue of such glycopolymers (glycodynamers) that could confer an adaptive character which would enable them to modify their constitution in response to external physical or chemical stimuli (temperature, pH, etc.)…”

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confidence: 99%

Glycodynamers: Fluorescent Dynamic Analogues of Polysaccharides

2008

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confidence: 99%

Glycodynamers: Fluorescent Dynamic Analogues of Polysaccharides

2008

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confidence: 99%

Stable and Potent Polyvalent Anthrax Toxin Inhibitors: Raft‐Inspired Domain Formation in Liposomes that Contain PEGylated Lipids

Rai¹,

Vance²,

Poon³

et al. 2008

Chemistry A European J

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The design of polyvalent molecules [1][2][3][4][5], consisting of multiple copies of a ligand attached to a suitable scaffold, represents a promising approach for designing potent inhibitors of pathogens and microbial toxins [1,[6][7][8][9][10][11]. Liposomes are particularly attractive scaffolds for designing polyvalent inhibitors [9,10,[12][13][14][15]; however, the poor colloidal stability of conventional liposomes and their short circulation times in vivo [16,17] are major obstacles limiting their therapeutic use. We describe the design of highly stable and active polyvalent anthrax toxin inhibitors based on liposomes incorporating polyethylene glycol (PEG)-functionalized lipids (PEGylated liposomes). Furthermore, drawing from the concept of lipid rafts [15,18,19] -domains that are believed to exist in cellular membranes -we have designed heterogeneous domain-containing PEGylated liposomes that are considerably more active than their homogeneous counterparts (Scheme 1). These raft-mimetic PEGylated polyvalent liposomes are attractive not only for designing inhibitors for toxins and pathogens, but also for the design of efficient targeted drug delivery systems.While liposomes have been investigated extensively for applications in drug delivery, as described above, conventional liposomes are limited in effectiveness because of their low colloidal stability and their rapid uptake by macrophage cells of the immune system, predominantly in the liver and spleen [20]. The ability to enhance the physical stability and extend the circulation lifetime through modification with PEG, achieved by using lipids with PEG attached to their hydrophilic head groups, has proven to be useful in the context of drug delivery [17,[20][21][22]. We first tested whether the use of PEGylated liposomes (Scheme 1b) would enable the design of stable and active polyvalent anthrax lethal toxin (LeTx) inhibitors.To that end, we made liposomes (100 nm diameter) composed of a 19:1 mixture of 1,2-Distearoyl-sn-Glycero-3-Phosphocholine (DSPC) and a pyridyl dithiopropionate derivative of L-α-Distearoyl Phosphatidylethanolamine-N-[Amino(Polyethylene Glycol)2000] (DSPE-PEG2000-PDP). We functionalized these liposomes with an inhibitory peptide HTSTYWWLDGAPC [9,23] (4.7%) that binds to the heptameric cell-binding component of anthrax toxin, [PA 63 ] 7 , thereby blocking the binding of the toxic enzyme lethal factor (LF). Inhibition of the binding of LF to [PA 63 ] 7 prevents the cytosolic delivery of LF, thereby inhibiting cell death. Peptide-functionalized PEGylated liposomes protected RAW264.7 cells from LeTx with a half maximal inhibitory concentration (IC 50 ) of about 35 nM on a per-peptide basis; control PEGylated liposomes functionalized with thioglycerol showed no inhibitory activity (Fig. 1a). Furthermore, as seen in Fig. 1a, the activity of the polyvalent PEGylated liposomes (Scheme 1b) was comparable to that of conventional (non-PEGylated) DSPC-based liposomes (Scheme 1a) with the same peptide density (20 nM), indicating that the use of ...

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“…Then, the buffer solution was replaced by the b-PAH solution which was acting as a multivalent ligand [42,43] bioconjugating the Fc-SAv layer. In contrast to the first FcSAv layer, the recognition-mediated assembly of b-PAH displayed a slower decrease in frequency reaching a plateau after 50 min.…”

Section: Resultsmentioning

confidence: 99%

Tuning the Unidirectional Electron Transfer at Interfaces with Multilayered Redox‐active Supramolecular Bionanoassemblies

Azzaroni

Álvarez

Abou-Kandil

et al. 2008

Adv Funct Materials

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In this work, we present a new strategy to construct redox‐active molecular platforms to be used as molecular rectifiers with tunable and amplifiable electronic readout. The approach is based on using ligand‐receptor biological interactions to bioconjugate electroactive bio‐inorganic building blocks onto metal electrodes. The stability of the self‐assembled interfacial architecture is provided by multivalent macromolecular ligands that act as scaffolds for building‐up the multilayered structures. The ability of these electroactive supramolecular architectures to generate a unidirectional current flow and tune the corresponding electronic readout was demonstrated by mediating and rectifying the electron transfer between redox donors in solution and the Au electrode. The redox centers incorporated into the assembled architecture in a topologically controlled manner are responsible for tuning the amplification of the rectified electronic readout, thus behaving as a tunable bio‐supramolecular diode. Our experimental results obtained with these redox‐active bio‐supramolecular architectures illustrate the versatility of molecular recognition‐directed assembly in combination with hybrid bio‐inorganic building blocks to construct highly functional interfacial architectures.

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Non‐Covalent Polyvalent Ligands by Self‐Assembly of Small Glycodendrimers: A Novel Concept for the Inhibition of Polyvalent Carbohydrate–Protein Interactions In Vitro and In Vivo

Cited by 36 publications

References 48 publications

Glycodynamers: Fluorescent Dynamic Analogues of Polysaccharides

Glycodynamers: Fluorescent Dynamic Analogues of Polysaccharides

Stable and Potent Polyvalent Anthrax Toxin Inhibitors: Raft‐Inspired Domain Formation in Liposomes that Contain PEGylated Lipids

Tuning the Unidirectional Electron Transfer at Interfaces with Multilayered Redox‐active Supramolecular Bionanoassemblies

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