Multivalent Interactions between Lectins and Supramolecular Complexes: Galectin-1 and Self-Assembled Pseudopolyrotaxanes

Belitsky, Jason M.; Nelson, Alshakim; Hernandez, Joseph D.; Baum, Linda G.; Stoddart, J. Fraser

doi:10.1016/j.chembiol.2007.09.007

Cited by 49 publications

(36 citation statements)

References 64 publications

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“…However, small fragments of natural oligosaccharides suffer from the drawback of typically low affinity (high mM to mM for galectins), limited chemical and metabolic stability, and high polarity leading to low bioavailability and rapid clearance. Multivalent inhibitors against galectins have almost exclusively been decorated with natural saccharides [28][29][30][31][32][33][34][35][36][37][38][39][40] and thus interact with the binding site as natural saccharides but in addition may or may not make use of the affinity-enhancing glycoside clustering effect. One exception is Pieter's development of galectin-targeting photoaffinitylabelling structures, which incorporated a photo-reactive and affinity-enhancing benzophenone ether at O(3') of multivalently presented lactosides.…”

Section: Inhibition Strategiesmentioning

confidence: 99%

Inhibition of Galectins with Small Molecules

Öberg¹,

Leffler²,

Nilsson³

2011

Chimia

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Evidence that the galectin family of proteins plays crucial roles in cancer, inflammation, and immunity has accumulated over the last decade. The galectins have consequently emerged as interesting drug targets. A majority of galectin functions occurs by means of cross-linking glycoproteins and by doing so controlling glycoprotein cellular localization and residence times. The glycoprotein cross-linking occurs when galectin dimers or multimers, or galectins with two binding sites, bind galactose-containing glycans of the glycoproteins. Such galectin-glycan interactions have been successfully blocked with compounds having multivalent presentation of galactose, lactose, or N-acetyllactosamine, with peptides, and with small carbohydrate (galactose) derivatives. This review summarizes and analyzes attempts to develop efficient and selective small-molecule galectin inhibitors through derivatization of monosaccharides, mainly galactosides, with non-carbohydrate structures that protrude into subsites adjacent to the core-conserved galactose-recognizing site of the galectins.

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Section: Inhibition Strategiesmentioning

confidence: 99%

Inhibition of Galectins with Small Molecules

Öberg¹,

Leffler²,

Nilsson³

2011

Chimia

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“…For this purpose, specific ligands or receptors, such as carbohydrate groups, could be combined with our fluorescent polyrotaxane, leading to very sensitive molecular probes. The affinities of polyrotaxanes with pending ligands toward biological surfaces are known to be higher than those affinities of monomeric ligands because of the cooperatively of binding of multiple ligands to multiple receptors on one another 52–54…”

Section: Discussionmentioning

confidence: 99%

Synthesis of a difunctional organolithium compound as initiator for the polymerization of styrene‐butadiene/isoprene‐styrene triblock copolymer

Lu¹,

Xu²,

Li³

et al. 2006

J of Applied Polymer Sci

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A difunctional organolithium compound was prepared by the addition of butyllithium (BuLi) to 1,4-bis(4-methyl-1-phenylethenyl)benzene (MPEB). The effects of the solvent, polar modifier (THF), butyl lithium structure, and reaction time on the formation of the difunctional organolithium compound were studied. Results showed that toluene as solvent was in favor of the addition reaction over cycohexane, in the absence of the polar modifier. However, cycohexane was a better option as solvent for the addition reaction, when polar modifier was employed. A small amount of polar modifier could efficiently accelerate the reaction rate and have no significant effect on the structure of the polydiene, which was initiated by the polar modifier containing organolithium compound. Results also showed that isobutyl lithium was more active in the addition reaction than n-butyl lithium, because of inductive effect. The optimum molar ratio of THF/Liϩ was determined as 4. The THF containing difunctional organolithium cyclohexane solution was sequentially used in the step-wise polymerization of triblock thermoplastic copolymer SIBS. The so-prepared SIBS shared the similar phase separation structure with SBS and exhibited excellent mechanic properties. As the content of the central polyisoprene block increases, the tensile strength of the copolymer is decreased, and the elongation at break is increased. The glass transition temperature T g of the central block was correlated with its content as T g ϭ 0.33 ϫ Ϫ62.81, where ϫ is the wt % of the central block, based on the triblock copolymer.

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“…A recent review summarises the strategy, limitations, and expectations of a multivalent display of galectin-binding saccharides. [44] Multivalent ligand display approaches utilised thus far have been bi-to tetravalent glycoclusters, [92][93][94][95][96] much larger glycoclusters such as wedge-like and starburst dendrimers that present 8-128 saccharides, [97,98] cyclodextrin-based glycoclusters, [99][100][101][102] calix[n]arene-based glycoclusters, [103][104][105] cyclic neoglycopeptides, [106,107] and cyclophanes and terephthalamides. [108] Consistently, one of three types of assays are reported to evaluate the galectin multivalent inhibitor efficiency: solid-phase competitive inhibition assay between immobilised glycoproteins and galectins, in vitro competitive assay where the inhibitor is competing against the binding of galectins to cell surface receptors, and haemagglutination inhibition assays.…”

Section: Glycodendrimersmentioning

confidence: 99%

Inhibitors of Galectins and Implications for Structure-Based Design of Galectin-Specific Therapeutics

2014

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Galectins are a family of galactoside-specific lectins that are involved in a myriad of metabolic and disease processes. Due to roles in cancer and inflammatory and heart diseases, galectins are attractive targets for drug development. Over the last two decades, various strategies have been used to inhibit galectins, including polysaccharide-based therapeutics, multivalent display of saccharides, peptides, peptidomimetics, and saccharide-modifications. Primarily due to galectin carbohydrate binding sites having high sequence identities, the design and development of selective inhibitors targeting particular galectins, thereby addressing specific disease states, is challenging. Furthermore, the use of different inhibition assays by research groups has hindered systematic assessment of the relative selectivity and affinity of inhibitors. This review summarises the status of current inhibitors, strategies, and novel scaffolds that exploit subtle differences in galectin structures that, in conjunction with increasing available data on multiple galectins, is enabling the feasible design of effective and specific inhibitors of galectins. small-molecule crystallography, University of London, UK) undertook post-doctoral research in protein X-ray crystallography and drug-design in academia and industry within Canada, USA, Switzerland and Australia. In 2002 Helen established a protein X-ray crystallography structural biology group at the Institute for Glycomics, Griffith University. As recognition of her international contribution to structural biology and chemistry she was admitted as fellow of the Royal Society of Chemistry (FRSC) in 2006. Her research involves determination of atomic protein structure, analysis of protein-ligand interactions and application of this information in understanding protein function and for structure based drug-design. Her research group has a major focus on lectins critical to disease progression including her research program on galectins that have importance in serious conditions including cancer. Khuchtumur Bum-Erdene completed his Bachelors degree in Chemistry (

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Multivalent Interactions between Lectins and Supramolecular Complexes: Galectin-1 and Self-Assembled Pseudopolyrotaxanes

Cited by 49 publications

References 64 publications

Inhibition of Galectins with Small Molecules

Inhibition of Galectins with Small Molecules

Synthesis of a difunctional organolithium compound as initiator for the polymerization of styrene‐butadiene/isoprene‐styrene triblock copolymer

Inhibitors of Galectins and Implications for Structure-Based Design of Galectin-Specific Therapeutics

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