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International audience; Selective DC-SIGN targeting vs. langerin might lead to anti-infective agents, given their counteracting effects upon infection by some pathogens. Here we show that multivalent sp2-iminosugar-containing mannobioside analogs can achieve total DC-SIGN selectivity by levering the canonic binding mode towards high-mannose oligosaccharide ligands, behaving as factual biomimics

The late-onset form of Tay-Sachs disease displays when the activity levels of human β-hexosaminidase A (HexA) fall below 10% of normal, due to mutations that destabilise the native folded form of the enzyme and impair its trafficking to the lysosome. Competitive inhibitors of HexA can rescue disease-causative mutant HexA, bearing potential as pharmacological chaperones, but often also inhibit the enzyme O-glucosaminidase (GlcNAcase; OGA), a serious drawback for translation into the clinic. We have designed sp

The architectural perfection and multivalency of dendrimers have made them useful for biodelivery via peripheral functionalization and the adjustment of dendrimer generations. Modulation of the core-forming and internal matrix-forming structures offers virtually unlimited opportunities for further optimization, but only in a few cases this has been made compatible with strict diastereomeric purity over molecularly diverse series, low toxicity, and limited synthetic effort. Fully regular star polymers built on biocompatible macrocyclic platforms, such as hyperbranched cyclodextrins, offer advantages in terms of facile synthesis and flexible compositions, but core elaboration in terms of shape and function becomes problematic. Here we report the synthesis and characterization of star polymers consisting of functional trehalose-based macrocyclic cores (cyclotrehalans, CTs) and aminothiourea dendron arms, which can be efficiently synthesized from sequential click reactions of orthogonal monomers, display no cytotoxicity, and efficiently complex and deliver plasmid DNA in vitro and in vivo. When compared with some commercial cationic dendrimers or polymers, the new CT-scaffolded star polymers show better transfection efficiencies in several cell lines and structure-dependent cell selectivity patterns. Notably, the CT core could be predefined to exert Zn(II) complexing or molecular inclusion capabilities, which has been exploited to synergistically boost cell transfection by orders of magnitude and modulate the organ tropism in vivo.

In many human carcinomas, mucin-1 (MUC1) is overexpressed and aberrantly glycosylated, resulting in the exposure of previously hidden antigens. This generates new patient antibody profiles that can be used in cancer diagnosis. In the present study, we focused on the MUC1-associated Tn antigen (α-O-GalNAc-Ser/Thr) and substituted the GalNAc monosaccharide by a glycomimic to identify MUC1-based glycopeptides with increased antigenicity. Two different glycopeptide libraries presenting the natural Tn antigen or the sp2-iminosugar analogue were synthesized and evaluated with anti-MUC1 monoclonal antibodies in a microarray platform. The most promising candidates were tested with healthy and breast cancer sera aiming for potential autoantibody-based biomarkers. The suitability of sp2-iminosugar glycopeptides to detect anti-MUC1 antibodies was demonstrated, and serological experiments showed stage I breast cancer autoantibodies binding with a specific unnatural glycopeptide with almost no healthy serum interaction. These results will promote further studies on their capabilities as early cancer biomarkers.

Owing to its roles in human health and disease, the modification of nuclear, cytoplasmic, and mitochondrial proteins with O-linked

We report the rational design and synthesis of C2-modified DGJ analogues to improve the selective inhibition of human GALA over other glycosidases. We prepare these analogues using a concise route from non-carbohydrate materials and demonstrate the most selective inhibitor 7c (∼100-fold) can act in Fabry patient cells to drive reductions in levels of the disease-relevant glycolipid Gb3.

The Tn antigen (GalNAc-α-1-O-Thr/Ser) is a well-known tumor-associated carbohydrate determinant. The use of glycopeptides that incorporate this structure has become a significant and promising niche of research owing to their potential use as anticancer vaccines. Herein, the conformational preferences of a glycopeptide with an unnatural Tn antigen, characterized by a threonine decorated with an sp2-iminosugar-type α-GalNAc mimic, have been studied both in solution, by combining NMR spectroscopy and molecular dynamics simulations, and in the solid state bound to an anti-mucin-1 (MUC1) antibody, by X-ray crystallography. The Tn surrogate can mimic the main conformer sampled by the natural antigen in solution and exhibits high affinity towards anti-MUC1 antibodies. Encouraged by these data, a cancer vaccine candidate based on this unnatural glycopeptide and conjugated to the carrier protein Keyhole Limpet Hemocyanin (KLH) has been prepared and tested in mice. Significantly, the experiments in vivo have proved that this vaccine elicits higher levels of specific anti-MUC1 IgG antibodies than the analog that bears the natural Tn antigen and that the elicited antibodies recognize human breast cancer cells with high selectivity. Altogether, we compile evidence to confirm that the presentation of the antigen, both in solution and in the bound state, plays a critical role in the efficacy of the designed cancer vaccines. Moreover, the outcomes derived from this vaccine prove that there is room for exploring further adjustments at the carbohydrate level that could contribute to designing more efficient cancer vaccines., An anti-cancer vaccine based on an unnatural antigen with an sp2-iminosugar fragment.

Inflammatory processes play a central role in the pathogenesis of diabetic nephropathy (DN) in the early stages of the disease. The authors demonstrate that the glycolipid mimetic (Ss)-DS-ONJ is able to abolish inflammation via the induction of autophagy flux and provokes the inhibition of inflammasome complex in ex vivo and in vitro models, using adult kidney explants from BB rats. The contribution of (Ss)-DS-ONJ to reducing inflammatory events is mediated by the inhibition of classical stress kinase pathways and the blocking of inflammasome complex activation. The (Ss)-DS-ONJ treatment is able to inhibit the epithelial-to-mesenchymal transition (EMT) progression, but only when the IL18 levels are reduced by the treatment. These findings suggest that (Ss)-DS-ONJ could be a novel, and multifactorial treatment for DN. Junta de Andalucía PI-0012-2019, PI20-01330, PI-0036-2020, P20_00166 Ministerio de Ciencia, Innovación y Universidades RTI2018- 097609-B-C21, PID2021-124247OB-C21

International audience; A highly enantioselective synthesis of (R,S) or (S,S)-2,6-disubstituted dehydropiperidines has been previously achieved through Sn/Li transmetalation of the corresponding stannylated dehydropiperidines or of their precursors. Herein, we successively consider their Upjohn's syn dihydroxylation and their anti-dihydroxylation via an epoxidation reaction followed by epoxide opening reaction. The stereochemical course of these reactions was first reported including the use of appropriate protecting groups before considering the conversion of the obtained compounds into NH or NMe iminosugar hydrochlorides. A primary evaluation of the designed iminosugar C-glycosides as glycosidase inhibitors suggests candidates for the selective inhibition of α-galactosidase, amyloglycosidase and naringinase. Beyond the reported results, the method constitutes a highly modulable route for the synthesis of well stereodefined iminosugar C-glycosides, an advantage which might be used for the design of iminosugars to enhance their biological properties.

Instilling segregated cationic and lipophilic domains with an angular disposition in a trehalose‐based trifaceted macrocyclic scaffold allows engineering patchy molecular nanoparticles leveraging directional interactions that emulate those controlling self‐assembling processes in viral capsids. The resulting trilobular amphiphilic derivatives, featuring a Mickey Mouse architecture, can electrostatically interact with plasmid DNA (pDNA) and further engage in hydrophobic contacts to promote condensation into transfectious nanocomplexes. Notably, the topology and internal structure of the cyclooligosaccharide/pDNA co‐assemblies can be molded by fine‐tuning the valency and characteristics of the cationic and lipophilic patches, which strongly impacts the transfection efficacy in vitro and in vivo. Outstanding organ selectivities can then be programmed with no need of incorporating a biorecognizable motif in the formulation. The results provide a versatile strategy for the construction of fully synthetic and perfectly monodisperse nonviral gene delivery systems uniquely suited for optimization schemes by making cyclooligosaccharide patchiness the focus., Mickey Mouse molecular nanoparticles with a trehalose‐based cyclooligosaccharide core and uneven distributions of cationic (C, red lobules) and lipophilic patches (L, blue lobules) co‐assemble with plasmid DNA (pDNA, orange chains) to afford transfectious nanacomplexes with programmable topologies and internal structures, ranging from multilamellar spheroids and rods to core‐shell arrangements, translating into amazing cell efficiencies in vitro and organ selectivities in vivo with no need of targeting labels.

A robust strategy is reported to build perfectly monodisperse star polycations combining a trehalose-based cyclooligosaccharide (cyclotrehalan, CT) central core onto which oligoethyleneimine radial arms are installed. The architectural perfection of the compounds is demonstrated by a variety of physicochemical techniques, including NMR, MS, DLS, TEM, and GPC. Key to the strategy is the possibility of customizing the cavity size of the macrocyclic platform to enable/prevent the inclusion of adamantane motifs. These properties can be taken into advantage to implement sequential levels of stimuli responsiveness by combining computational design, precision chemistry and programmed host-guest interactions. Specifically, it is shown that supramolecular dimers implying a trimeric CT-tetraethyleneimine star polycation and purposely designed bis-adamantane guests are preorganized to efficiently complex plasmid DNA (pDNA) into transfection-competent nanocomplexes. The stability of the dimer species is responsive to the protonation state of the cationic clusters, resulting in dissociation at acidic pH. This process facilitates endosomal escape, but reassembling can take place in the cytosol then handicapping pDNA nuclear import. By equipping the ditopic guest with a redox-sensitive disulfide group, recapturing phenomena are prevented, resulting in drastically improved transfection efficiencies both in vivo and in vitro.

Original molecular vectors that ensure broad flexibility to tune the shape and surface properties of plasmid DNA (pDNA) condensates are reported herein. The prototypic design involves a cyclodextrin (CD) platform bearing a polycationic cluster at the primary face and a doubly linked aromatic module bridging two consecutive monosaccharide units at the secondary face that behaves as a topology-encoding element. Subtle differences at the molecular level then translate into disparate morphologies at the nanoscale, including rods, worms, toroids, globules, ellipsoids, and spheroids. In vitro evaluation of the transfection capabilities revealed marked selectivity differences as a function of nanocomplex morphology. Remarkably high transfection efficiencies were associated with ellipsoidal or spherical shapes with a lamellar internal arrangement of pDNA chains and CD bilayers. Computational studies support that the stability of such supramolecular edifices is directly related to the tendency of the molecular vector to form noncovalent dimers upon DNA templating. Because the stability of the dimers depends on the protonation state of the polycationic clusters, the coaggregates display pH responsiveness, which facilitates endosomal escape and timely DNA release, a key step in successful transfection. The results provide a versatile strategy for the construction of fully synthetic and perfectly monodisperse nonviral gene delivery systems uniquely suited for optimization schemes.

An ultra-fast synthetic procedure based on grafting of twelve fullerene macromonomers onto a fullerene hexa-adduct core was used for the preparation of a giant molecule with 120 peripheral iminosugar residues. The inhibition profile of this giant iminosugar ball was evaluated against various glycosidases. In the particular case of the Jack bean α-mannosidase, a dramatic enhancement of the glycosidase inhibitory effect was observed for the giant molecule with 120 peripheral subunits as compared to that of the corresponding mono- and dodecavalent model compounds., We acknowledge the financial support from the Spanish Ministerio de Economía y Competitividad (MINECO; contracts SAF2016-76083-R and CTQ2015-64425-C2-1-R), the Junta de Andalucía (contract FQM2012-1467), the CITIUS, the Biomolecular Interactions Platform (CicCartuja), the CNRS, the University of Strasbourg, the International Center for Frontier Research in Chemistry and the LabEx “Chimie des Systèmes Complexes”.

It has been amply constated that sugar ligand multivalency increases lectin-binding avidities dramatically, thereby modulating the capacity of carbohydrates to participate in supramolecular recognition processes involving transfer of biological information. The importance of this concept, the multivalent or glycoside cluster effect, in cell biology in general and in the glycosciences in particular is reflected in the ever-growing number of papers in the field. An impressive range of glycoarchitectures has been conceived to imitate the glycan coating of cells (the glycocalyx) in order to target complementary lectin receptors. However, these models rarely address the heterogeneity and the fluidity of the densely glycosylated cell membrane. They also disregard the impact that high-density nanosized arrangements could have in their interactions with the whole spectrum of carbohydrate-interacting proteins, among which glycosidases are notable representatives. For many years it has been tacitly assumed that: (i) efficient recognition by lectins generally requires high densities of the putative primary ligand and (ii) the mechanisms governing binding of a carbohydrate motif by a lectin or a glycosidase are totally disparate. Notwithstanding, an increasing amount of evidence seriously questions this paradigm. First, it was shown that secondary “innocent” ligands can play important roles in the recognition of heteroglycocluster constructs by lectins through synergistic or antagonistic contributions, a phenomenon termed the heterocluster effect. Second, the existence of multivalent effects in the inhibition of certain glycosidases by glycomimetic- and, even more disturbing, glyco-coated architectures (multivalent enzyme inhibition) was demonstrated. These observations call for a generalized multivalent effect governing the supramolecular chemistry of carbohydrate or glycomimetic structures in a biological context, with (hetero)multivalency acting as a multimodal switcher to drive the encoded information through different pathways. In this Feature Article we review the advancements made in the last few years in our understanding of the mechanisms underpinning the generalized multivalent effect, with an emphasis on the potential risks and opportunities derived from (hetero)multivalency-elicited promiscuity. Unión Europea, (MICIU, AEI, FEDER, UE). RTI2018- 097609-B-C21 Union Europea, MINECO, FEDER contract numbers SAF2016-76083-R

This chapter summarizes the implemented synthetic strategies aimed at generating molecular diversity in a new family of stable glycoconjugate mimetics, namely sp2-iminosugar glycolipids and glycopeptides. It further illustrates the potential of these compounds as antitumor, antileishmanial, and anti-inflammatory agents. The presence of a pseudoamide functionality at the place of the endocyclic oxygen atom typical of monosaccharides makes sp2-iminosugars very good substrates for glycosylation reactions. Structure-activity relationship studies have revealed strong effects of the nature of glycosidic linkage (N, S, C, SO, SO2) and the aglycone moiety in the biological properties. The mechanisms of action are also discussed, pointing at p38α mitogen-activated protein kinase as a main pharmacological target.

© 2020 by the authors., Small interfering ribonucleic acid (siRNA) has the potential to revolutionize therapeutics since it can knockdown very efficiently the target protein. It is starting to be widely used to interfere with cell infection by HIV. However, naked siRNAs are unable to get into the cell, requiring the use of carriers to protect them from degradation and transporting them across the cell membrane. There is no information about which is the most efficient endocytosis route for high siRNA transfection efficiency. One of the most promising carriers to efficiently deliver siRNA are cyclodextrin derivatives. We have used nanocomplexes composed of siRNA and a β-cyclodextrin derivative, AMC6, with a very high transfection efficiency to selectively knockdown clathrin heavy chain, caveolin 1, and p21 Activated Kinase 1 to specifically block clathrin-mediated, caveolin-mediated and macropinocytosis endocytic pathways. The main objective was to identify whether there is a preferential endocytic pathway associated with high siRNA transfection efficiency. We have found that macropinocytosis is the preferential entry pathway for the nanoparticle and its associated siRNA cargo. However, blockade of macropinocytosis does not affect AMC6-mediated transfection efficiency, suggesting that macropinocytosis blockade can be functionally compensated by an increase in clathrin- and caveolin-mediated endocytosis., This research was funded, in part, by contract numbers PID2019-105858RB-I00 (MCI, AEI, FEDER, UE) and RTI2018-097609-B-C21 (MICIU, AEI, FEDER, UE) to C.O.M. and J.M.G.F. and grants from the Spanish Ministerio de Economía y Competitividad (project SAF2017-89288-R from MINECO/AEI/FEDER/UE), from Junta de Comunidades de Castilla-La Mancha (project SBPLY/19/180501/000067), and ISCIII (AC19/00075) and ERANET Euronanomed Program (project NANO4GLIO) to V.C. It also benefited from the framework of COST Action Nano2Clinic (CA17140), supported by COST (European Cooperation in Science and Technology)., Publisher’s version

This journal is © The Royal Society of Chemistry 2020. This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence., The Tn antigen (GalNAc-α-1-O-Thr/Ser) is a well-known tumor-associated carbohydrate determinant. The use of glycopeptides that incorporate this structure has become a significant and promising niche of research owing to their potential use as anticancer vaccines. Herein, the conformational preferences of a glycopeptide with an unnatural Tn antigen, characterized by a threonine decorated with an sp2-iminosugar-type α-GalNAc mimic, have been studied both in solution, by combining NMR spectroscopy and molecular dynamics simulations, and in the solid state bound to an anti-mucin-1 (MUC1) antibody, by X-ray crystallography. The Tn surrogate can mimic the main conformer sampled by the natural antigen in solution and exhibits high affinity towards anti-MUC1 antibodies. Encouraged by these data, a cancer vaccine candidate based on this unnatural glycopeptide and conjugated to the carrier protein Keyhole Limpet Hemocyanin (KLH) has been prepared and tested in mice. Significantly, the experiments in vivo have proved that this vaccine elicits higher levels of specific anti-MUC1 IgG antibodies than the analog that bears the natural Tn antigen and that the elicited antibodies recognize human breast cancer cells with high selectivity. Altogether, we compile evidence to confirm that the presentation of the antigen, both in solution and in the bound state, plays a critical role in the efficacy of the designed cancer vaccines. Moreover, the outcomes derived from this vaccine prove that there is room for exploring further adjustments at the carbohydrate level that could contribute to designing more efficient cancer vaccines., We acknowledge the Ministerio de Ciencia, Innovación y Universidades and the Agencia Estatal de Investigación (projects RTI2018-099592-B-C21 and RTI2018-097609-B-C21), the Ministerio de Economía y Competitividad (SAF2016-76083-R), European Regional Development Funds (FEDER-UE), the Royal Society (URF\R\180019 to G. J. L. B.) and FCT Portugal (PhD studentship, SFRH/BD/115932/2016 to A. G. and FCT Investigator IF/00624/2015 to G. J. L. B.). M. C. O further thanks CITIUS for technical support. I. A. B. thanks the Asociación Española Contra el Cancer en La Rioja for a grant. E. J.-M. thanks Universidad de La Rioja for a postdoctoral fellowship. R. H.-G. acknowledges Diamond Light Source (Oxford, UK) synchrotron beamline I04 (experiment numbers mx10121-19). He also acknowledges ARAID, MEC (CTQ2013-44367-C2-2-P and BFU2016-75633-P) and Gobierno de Aragón (E34_R17 and LMP58_18) with FEDER (2014–2020) funds for ‘Building Europe from Aragón’ for financial support. The research leading to these results has also received funding from FP7 442 (2007–2013) under BioStruct-X (grant agreement no. 283570 and BIOSTRUCTX_5186). F. G.-M. of Hokkaido University acknowledges grant from the Naito Foundation.

The irradiation of concentrated feeds of carbohydrates in alcoholic solution by high-frequency ultrasound (550 kHz) induces the formation of alkylpolyglycosides (APGs). This work is distinct from previous reports in that it does not involve any (bio)catalyst or activating agent, it takes place at only 40 °C, thus avoiding degradation of carbohydrates, and it selectively yields APGs with a degree of polymerization in a window of 2¿7, an important limitation of the popular Fischer glycosylation. This ultrasound-based technology proved successful with a range of different valuable carbohydrates and alkyl alcohols. The elucidation of the structure of all the produced glycosides strongly suggests that 1,6-anhydrosugars formed in situ are key intermediate species., Authors are grateful to the CNRS, the University of Poitiers, the Ministry of Research, the Région Nouvelle Aquitaine, the MINECO (contract nos. SAF2016‐76083‐R and CTQ2015‐64425‐C2‐1‐R), the Junta de Andalucía (contract no. FQM2012‐1467) and the European Community (FEDER) for their financial supports.

Engineering self-assembled superstructures through complexation of plasmid DNA (pDNA) and single-isomer nanometric size macromolecules (molecular nanoparticles) is a promising strategy for gene delivery. Notably, the functionality and overall architecture of the vector can be precisely molded at the atomic level by chemical tailoring, thereby enabling unprecedented opportunities for structure/self-assembling/pDNA delivery relationship studies. Beyond this notion, by judiciously preorganizing the functional elements in cyclodextrin (CD)-based molecular nanoparticles through covalent dimerization, here we demonstrate that the morphology of the resulting nanocomplexes (CDplexes) can be tuned, from spherical to ellipsoidal, rod-type, or worm-like nanoparticles, which makes it possible to gain understanding of their shape-dependent transfection properties. The experimental findings are in agreement with a shift from chelate to cross-linking interactions on going from primary-face- to secondary-face-linked CD dimers, the pDNA partner acting as an active payload and as a template. Most interestingly, the transfection efficiency in different cells was shown to be differently impacted by modifications of the CDplex morphology, which has led to the identification of an optimal prototype for tissue-selective DNA delivery to the spleen in vivo., This study was supported by the Spanish Ministerio de Economía y Competitividad (contract numbers CTQ2012‐30821, CTQ2015‐65972‐R, SAF2016‐76083‐R, CTQ2015‐64425‐C2‐1‐R, and CTQ2015‐64425‐C2‐2‐R), the Junta de Andalucía (contract number FQM2012‐1467), the University Complutense of Madrid (project no. UCMA05‐33‐010), and the European Regional Development Funds (FEDER and FSE).

Amphiphilic glycomimetics encompassing a rigid, undistortable nor-tropane skeleton based on 1,6-anhydro-L-idonojirimycin and a polyfluorinated antenna, when formulated as the corresponding inclusion complexes with β-cyclodextrin (βCD), have been shown to behave as pharmacological chaperones (PCs) that efficiently rescue lysosomal β- glucocerebrosidase mutants associated to the neuronopathic variants of Gaucher disease (GD), including the highly refractory L444P/L444P and L444P/P415R single nucleotide polymorphs, in patient fibroblasts. The body of work here presented includes the design criteria for the PC prototype, the synthesis of a series of candidates, the characterization of the PC:βCD complexes, the determination of the selectivity profiles towards a panel of commercial and human lysosomal glycosidases, the evaluation of the chaperoning activity in type 1 (non-neuronopathic), 2 (acute neuronopathic) and 3 (adult neuronopathic) GD fibroblasts, the confirmation of the rescuing mechanism by immunolabeling and the analysis of the PC:GCase binding mode by docking experiments., The Spanish Ministerio de Economıa y Competitividad (MINECO; Contracts SAF2016-76083-R, CTQ2015-64425-C2-1-R, BFU2015-71017-P, and CTQ2013-43310), the Spanish Ministerio de Sanidad (Contract FIS PI13/00129), the Junta de Andalucıa (Contracts CTS-5725, FQM2012-1467, and BIO-198), the Generalitat Valenciana (PROMETEOII/2014/073), the Ministry of Education, Culture, Science, Sports and Technology of Japan (KAKENHI), the Ministry of Health, Labour and Welfare of Japan (Grants H17-Kokoro-019, H20-Kokoro-022), and the European Union Seventh Framework Programme (FP7-People-2012-CIG), Grant 333594 (to E.M.S.-F., Marie Curie Reintegration Grant) are acknowledged. Cofinancing from the European Regional Development Funds (FEDER and FSE) is also acknowledged. K.H. was supported by Takeda Science Foundation.

Immunomodulatory glycolipids, among which α-galactosylceramide (KRN7000) is an iconic example, have shown strong therapeutic potential in a variety of conditions ranging from cancer and infection to autoimmune or neurodegenerative diseases. A main difficulty for those channels is that they often provoke a cytokine storm comprising both pro- and anti-inflammatory mediators that antagonize each other and negatively affect the immune response. The synthesis of analogues with narrower cytokine secretion-inducing capabilities is hampered by the intrinsic difficulty at controlling the stereochemical outcome in glycosidation reactions, particularly if targeting the α-anomer, which seriously hampers drug optimization strategies. Here we show that replacing the monosaccharide glycone by a sp

An original family of multivalent vectors encompassing gemini and facial amphiphilicity, namely cationic Siamese twin surfactants, has been prepared fromthe disaccharide trehalose;molecular engineering lets us modulate the self-assembling properties and the topology of the nanocomplexes with plasmid DNA for efficient gene delivery in vitro and in vivo., The authors thank MINECO/MCIU (SAF2016-76083-R, CTQ2015-64425-C2-1-R, CTQ2015-64425-C2-2-R, RTI2018-097609-B-C21 and RTI2018-097609-B-C22), the Junta de Andalucía (FQM2012-1467) and the European Regional Development Funds (FEDER and FSE) for financial support. We acknowledge the CSIC (URICI) for supporting open access publication and the CITIUS (Univ. Seville) for technical support.

The presence of a doubly-linked naphthylene clip at the O-2I and O-3II positions in the secondary ring of β-cyclodextrin (βCD) derivatives promoted their self-assembly into head-to-head supramolecular dimers in which the aromatic modules act either as cavity extension walls (if the naphthalene moiety is 1,8-disubstituted) or as folding screens that separate the individual βCD units (if 2,3-disubstituted). Dimer architecture is governed by the conformational properties of the monomer constituents, as determined by NMR, fluorescence, circular dichroism, and computational techniques. In a second supramolecular organization level, the topology of the assembly directs host-guest interactions and, reciprocally, guest inclusion impacts the stability of the supramolecular edifice. Thus, inclusion of adamantane carboxylate, a well-known βCD cavity-fitting guest, was found to either preserve the dimeric arrangement, leading to multicomponent species, or elicit dimer disruption. The ensemble of results highlights the potential of the approach to program self-organization and external stimuli responsiveness of CD devices in a controlled manner while keeping full diastereomeric purity. Spanish Ministerio de Economía y Competitividad CTQ2015-64425-C2-1-R, CTQ2016-80600-P and SAF2016- 76083-R Junta de Andalucía contract number FQM2012-1467 UAH CCGP2017-EXP/027

Glycolipid mimetics consisting of a bicyclic polyhydroxypiperidine-cyclic carbamate core and a pseudoanomeric hydrophobic tail, termed sp

α-Mannosidosis (AM) results from deficient lysosomal α-mannosidase (LAMAN) activity and subsequent substrate accumulation in the lysosome, leading to severe pathology. Many of the AM-causative mutations compromise enzyme folding and could be rescued with purpose-designed pharmacological chaperones (PCs). We found that PCs combining a LAMAN glycone-binding motif based on the 5N,6O-oxomethylidenemannojirimycin (OMJ) glycomimetic core and different aglycones, in either mono- or multivalent displays, elicit binding modes involving glycone and nonglycone enzyme regions that reinforce the protein folding and stabilization potential. Multivalent derivatives exhibited potent enzyme inhibition that generally prevailed over the chaperone effect. On the contrary, monovalent OMJ derivatives with LAMAN aglycone binding area-fitting substituents proved effective as activity enhancers for several mutant LAMAN forms in AM patient fibroblasts and/or transfected MAN2B1-KO cells. This translated into a significant improvement in endosomal/lysosomal function, reverting not only the primary LAMAN substrate accumulation but also the additional downstream consequences such as cholesterol accumulation. Ministerio de Economía y Competitividad SAF2016-76083-R, CTQ2015-64425-C2-1-R Junta de Andalucía FQM2012-1467 Japan Society for the Promotion of Science 17K10051

[Image: see text] “Orphan” does not mean infrequent: over 7000 rare diseases affect millions of individuals. The US Orphan Drug Act and analogous regulations have succeeded at accelerating the development of novel therapies, but high prices threaten sustainability. Lysosomal storage disorders serve here to illustrate the light and shadows of this burgeoning field.

The judicious combination of shaping and recognition elements in cage-type architectures represents a powerful strategy to access molecular devices with tailored receptor properties and controlled abilities to form supramolecular assemblies. Aromatic modules are particularly attractive for these endeavors: they can play the role of rigid walls to build permanent cavities, folding screens between preexisting compartments and/or act as functional components promoting noncovalent self-interactions as well as associations with third species, allowing several levels of organization to be implemented. The field of cyclodextrins has enormously benefitted from the amalgamation with aromatic building blocks to give birth to hybrids with a much broader spectrum of properties and applications. The progress in precision chemistry has further enabled the efficient preparation of multiply-linked cap, hinge or clip cyclodextrin-aromatic chimeras with unprecedented level of control, which has translated into new developments in fields like supramolecular catalysis, self-assembly or gene delivery. This review article focuses specifically in these type of compounds, highlighting the intimate relationship between structure, supramolecular properties and performance in the target application. Ministerio de Economía y Competitividad CTQ2015-64425-C2-1-R, SAF2016-76083-R Junta de Andalucía FQM2012-1467

Multivalentmannosideswith inherentmacrophage recognition abilities, built on b-cyclodextrin, RAFT cyclopeptide or peptide dendrimer cores, trigger selective inhibition of lysosomal b-glucocerebrosidase or a-mannosidase depending on valency and topology, offering new opportunities in multitargeted drug design, The authors thank MINECO and MCIU/AEI (SAF2016-76083-R and RTI2018-097609-B-C21), the Junta de Andalucía (FQM2012-1467), the European Regional Development Funds (FEDER and FSE, UE), CNRS, Université Grenoble Alpes, ICMG FR 2607, the French ANR project Glyco@Alps (ANR-15-IDEX-02), Labex ARCANE, CBH-EUR-GS (ANR-17-EURE-0003), the COST action GLYCONanoPROBES (CM18132) and the JSPS KAKENHI Grant 17K10051 for financial support. We acknowledge the CSIC (URICI) for supporting open access publication and the CITIUS (Univ. Seville) for technical support. O. R. acknowledges the European Research Council Consolidator Grant “LEGO” (647938) for D. G. M. G.-C. is a FPI fellow

The unique stereoelectronic properties of sp2-iminosugars enable their participation in glycosylation reactions, thereby behaving as true carbohydrate chemical mimics. Among sp2-iminosugar conjugates, the sp2-iminosugar glycolipids (sp2-IGLs) have shown a variety of interesting pharmacological properties ranging from glycosidase inhibition to antiproliferative, antiparasitic, and anti-inflammatory activities. Developing strategies compatible with molecular diversity-oriented strategies for structure&ndash, activity relationship studies was therefore highly wanted. Here we show that a reaction sequence consisting in stereoselective C-allylation followed by thiol-ene &ldquo, click&rdquo, coupling provides a very convenient access to &alpha, C-glycoside sp2-IGLs. Both the glycone moiety and the aglycone tail can be modified by using sp2-iminosugar precursors with different configurational profiles (d-gluco or d-galacto in this work) and varied thiols, as well as by oxidation of the sulfide adducts (to the corresponding sulfones in this work). A series of derivatives was prepared in this manner and their glycosidase inhibitory, antiproliferative and antileishmanial activities were evaluated in different settings. The results confirm that the inhibition of glycosidases, particularly &alpha, glucosidase, and the antitumor/leishmanicidal activities are unrelated. The data are also consistent with the two later activities arising from the ability of the sp2-IGLs to interfere in the immune system response in a cell line and cell context dependent manner.

Cyclodextrin-calixarene giant amphiphiles that can self-assemble into nanospheres or nanovesicles have the ability to encapsulate the anticancer hydrophobic drugs docetaxel, temozolomide and combretastatin A-4 with encapsulation efficiencies >80% and deliver them to tumoral cells, enhancing their therapeutic efficacy by 1-3 orders of magnitude. These amphiphiles were modified by inserting a disulfide bridge confering them redox responsiveness. Disassembly of the resulting nanocompounds and cargo release was favored by high glutathione levels mimicking those present in the tumor microenvironment. Anticancer drug-loaded nanoformulations inhibited prostate, breast, glioblastoma, colon or cervix cancer cell lines proliferation with IC50 values markedly below those observed for the free drugs. Cell-cycle analysis indicated a similar mechanism of action for drug-loaded nanocompounds and free drugs. The results strongly suggest that the cyclodextrin-calixarene heterodimer prototype is an excellent scaffold for nanoformulations aimed to deliver anticancer drugs with limited bioavailability due to low solubility to tumoral cells, markedly increasing their effectivity.

Amphiphilic cyclodextrins (CDs) are biocompatible derivatives of natural CDs and are able to form nanoparticles or polyplexes spontaneously. In this study, nanoparticles prepared from nonionic (6OCapro beta CD) or cationic amphiphilic CD (PC bCDC6) were used comparatively to develop nanoparticles intended for breast cancer therapy. The characterization of these nanoparticles was performed both by in vitro and cell culture studies. Furthermore, the apoptotic and cytotoxic effects of blank amphiphilic CDs were demonstrated by various mechanistic methods including Caspase-8 activity, lipid peroxidation assay, TUNEL assay, Tali (R)-based image analysis, cholesterol assay, and gene expression studies. Blank nanoparticles exerted cytotoxicity against a variety of cancer cells (MCF-7, HeLa, HepG2, and MB49) but none to healthy cells (L929, G/G). Interestingly, blank 6OCapro beta CD and blank PC bCDC6 derivatives were found to be intrinsically effective on cell number and membrane integrity of MCF-7 cells in apoptosis studies. Further in-depth studies were performed to elucidate the selective mechanism of anticancer action in MCF-7 cells caused by these amphiphilic CDs. In conclusion, blank amphiphilic CD nanoparticles induced apoptosis through mitochondrial pathway targeted to cholesterol microdomains in cancer cell membrane. (C) 2016 American Pharmacists Association (R). Published by Elsevier Inc. All rights reserved.

We have investigated the effect of non-thermal atmospheric plasma (NTAP) on the structure of microcrystalline cellulose. In particular, by means of different characterization methods, we demonstrate that NTAP promotes the partial cleavage of the β-1,4 glycosidic bond of cellulose leading to the release of short-chain cellodextrins that are reassembled in situ, preferentially at the C6 position, to form branched glucans with either a glucosyl or anhydroglucosyl terminal residue. The ramification of cellulosic chain induced by NTAP yields branched glucans that are soluble in DMSO or in water, thus opening a straightforward access to processable glucans from cellulose. Importantly, the absence of solvent and catalyst considerably facilitates downstream processing as compared to (bio)catalytic processes which typically occur in diluted conditions.

Glycosidases are key enzymes in metabolism, pathogenic/antipathogenic mechanisms and normal cellular functions. Recently, a novel approach for glycosidase inhibition that conveys multivalent glycomimetic conjugates has emerged. Many questions regarding the mechanism(s) of multivalent enzyme inhibition remain unanswered. Herein we report the synthesis of a collection of novel homo- and heterovalent glyco(mimetic)-fullerenes purposely conceived for probing the contribution of non-catalytic pockets in glysosidases to the multivalent inhibitory effect. Their affinities towards selected glycosidases were compared with data from homovalent fullerene conjugates. An original competitive glycosidase–lectin binding assay demonstrated that the multivalent derivatives and the substrate compete for low affinity non-glycone binding sites of the enzyme, leading to inhibition by a “recognition and blockage” mechanism. Most notably, this work provides evidence for enzyme inhibition by multivalent glycosystems, which will likely have a strong impact in the glycosciences given the utmost relevance of multivalency in Nature., We thank the People Programme (Marie Curie Actions) of the European Union's Seventh Framework Programme FP7/2007‐2013/ under REA grant agreement no. 289033 and COST Action CM‐1102 MultiGlycoNano for the financial support. We also acknowledge financial support from the Spanish Ministerio de Economía y Competitividad (contract numbers SAF2013‐44021‐R and CTQ2015‐64425‐C2‐1‐R), the Junta de Andalucía (contract number FQM2012‐1467) and the European Regional Development Funds (FEDER and FSE).