- Sweet Drugs for Bad Bugs: A Glycomimetic Strategy against the DC-SIGN-Mediated Dissemination of SARS-CoV-2
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The C-type lectin receptor DC-SIGN is a pattern recognition receptor expressed on macrophages and dendritic cells. It has been identified as a promiscuous entry receptor for many pathogens, including epidemic and pandemic viruses such as SARS-CoV-2, Ebola virus, and HIV-1. In the context of the recent SARS-CoV-2 pandemic, DC-SIGN-mediated virus dissemination and stimulation of innate immune responses has been implicated as a potential factor in the development of severe COVID-19. Inhibition of virus binding to DC-SIGN, thus, represents an attractive host-directed strategy to attenuate overshooting innate immune responses and prevent the progression of the disease. In this study, we report on the discovery of a new class of potent glycomimetic DC-SIGN antagonists from a focused library of triazole-based mannose analogues. Structure-based optimization of an initial screening hit yielded a glycomimetic ligand with a more than 100-fold improved binding affinity compared to methyl α-d-mannopyranoside. Analysis of binding thermodynamics revealed an enthalpy-driven improvement of binding affinity that was enabled by hydrophobic interactions with a loop region adjacent to the binding site and displacement of a conserved water molecule. The identified ligand was employed for the synthesis of multivalent glycopolymers that were able to inhibit SARS-CoV-2 spike glycoprotein binding to DC-SIGN-expressing cells, as well as DC-SIGN-mediated trans-infection of ACE2+ cells by SARS-CoV-2 spike protein-expressing viruses, in nanomolar concentrations. The identified glycomimetic ligands reported here open promising perspectives for the development of highly potent and fully selective DC-SIGN-targeted therapeutics for a broad spectrum of viral infections.
- Cramer, Jonathan,Lakkaichi, Adem,Aliu, Butrint,Jakob, Roman P.,Klein, Sebastian,Cattaneo, Ivan,Jiang, Xiaohua,Rabbani, Said,Schwardt, Oliver,Zimmer, Gert,Ciancaglini, Matias,Abreu Mota, Tiago,Maier, Timm,Ernst, Beat
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p. 17465 - 17478
(2021/11/04)
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- New [(η5-C5H5)Ru(N-N)(PPh3)][PF6] compounds: Colon anticancer activity and GLUT-mediated cellular uptake of carbohydrate-appended complexes
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Eight ruthenium(ii) compounds of the general formula [(η5-C5H5)Ru(N-N)(PPh3)][PF6] were rationally designed, exhibiting high cytotoxicity against HCT116 human colon cancer cells, with IC50
- Florindo, Pedro R.,Pereira, Diane M.,Borralho, Pedro M.,Costa, Paulo J.,Piedade,Rodrigues, Cecília M. P.,Fernandes, Ana C.
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p. 11926 - 11930
(2016/08/05)
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- Importance of topology for glycocluster binding to Pseudomonas aeruginosa and Burkholderia ambifaria bacterial lectins
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Pseudomonas aeruginosa (PA) and Burkholderia ambifaria (BA) are two opportunistic Gram negative bacteria and major infectious agents involved in lung infection of cystic fibrosis patients. Both bacteria can develop resistance to conventional antibiotherap
- Ligeour, Caroline,Dupin, Lucie,Angeli, Anthony,Vergoten, Gérard,Vidal, Sébastien,Meyer, Albert,Souteyrand, Eliane,Vasseur, Jean-Jacques,Chevolot, Yann,Morvan, Fran?ois
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p. 11244 - 11254
(2015/11/27)
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- Gold nanoparticles decorated with mannose-6-phosphate analogues
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Herein, the preparation of neoglycoconjugates bearing mannose-6-phosphate analogues is described by: (a) synthesis of a cyclic sulfate precursor to access the carbohydrate head-group by nucleophilic displacement with an appropriate nucleophile; (b) introduction of spacers on the mannose-6-phosphate analogues via Huisgen's cycloaddition, the Julia reaction, or the thiol-ene reaction under ultrasound activation. With the resulting compounds in hand, gold nanoparticles could be functionalized with various carbohydrate derivatives (glycoconjugates) and then tested for angiogenic activity. It was observed that the length and flexibility of the spacer separating the sugar analogue from the nanoparticle have little influence on the biological response. One particular nanoparticle system substantially inhibits blood vessel growth in contrast to activation by the corresponding monomeric glycoconjugate, thereby demonstrating the importance of multivalency in angiogenic activity.
- Combemale, Stephanie,Assam-Evoung, Jean-Norbert,Houaidji, Sabrina,Bibi, Rashda,Barragan-Montero, Veronique
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p. 1120 - 1149
(2014/02/14)
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- Discovery of two classes of potent glycomimetic inhibitors of pseudomonas aeruginosa LecB with distinct binding modes
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The treatment of infections due to the opportunistic pathogen Pseudomonas aeruginosa is often difficult, as a consequence of bacterial biofilm formation. Such a protective environment shields the bacterium from host defense and antibiotic treatment and secures its survival. One crucial factor for maintenance of the biofilm architecture is the carbohydrate-binding lectin LecB. Here, we report the identification of potent mannose-based LecB inhibitors from a screening of four series of mannosides in a novel competitive binding assay for LecB. Cinnamide and sulfonamide derivatives are inhibitors of bacterial adhesion with up to a 20-fold increase in affinity to LecB compared to the natural ligand methyl mannoside. Because many lectins of the host require terminal saccharides (e.g., fucosides), such capped structures as reported here may offer a beneficial selectivity profile for the pathogenic lectin. Both classes of compounds show distinct binding modes at the protein, offering the advantage of a simultaneous development of two new lead structures as anti-pseudomonadal drugs with an anti-virulence mode of action.
- Hauck, Dirk,Joachim, Ines,Frommeyer, Benjamin,Varrot, Annabelle,Philipp, Bodo,Moeller, Heiko M.,Imberty, Anne,Exner, Thomas E.,Titz, Alexander
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p. 1775 - 1784
(2013/09/12)
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- GLYCOMIMETICS AS PSEUDOMONAS AERUGINOSA LECTIN INHIBITORS
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The present invention relates to fucose- and mannose-derived glycomimetics and their general use in prophylaxis or treatment of Pseudomonas aeruginosa infections including respiratory tract infections, urinary tract infections, nosocomial infections and chronic wound infections in a patient encompassing a patient suffering already from cystic fibrosis. Said glycomimetics are inhibitors of Pseudomonas aeruginosa lectin LecB.
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Page/Page column 19
(2013/11/05)
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- Glycomimetics as pseudomonas Aeruginosa lectin inhibitors
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The present invention relates to fucose- and mannose-derived glycomimetics and their general use in prophylaxis or treatment of Pseudomonas aeruginosa infections including respiratory tract infections, urinary tract infections, nosocomial infections and chronic wound infections in a patient encompassing a patient suffering already from cystic fibrosis. Said glycomimetics are inhibitors of Pseudomonas aeruginosa lectin LecB.
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Paragraph 0069
(2013/11/05)
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- Towards a stable noeuromycin analog with a d-manno configuration: Synthesis and glycosidase inhibition of d-manno-like tri- and tetrahydroxylated azepanes
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Noeuromycin is a highly potent albeit unstable glycosidase inhibitor due to its hemiaminal function. While stable d-gluco-like analogs have been reported, no data are available for d-manno-like structures. A series of tri- and tetrahydroxylated seven-memb
- Deschamp, Julia,Mondon, Martine,Nakagawa, Shinpei,Kato, Atsushi,Alonzi, Dominic S.,Butters, Terry D.,Zhang, Yongmin,Sollogoub, Matthieu,Blériot, Yves
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p. 641 - 649
(2012/03/11)
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- Quantifying the electronic effects of carbohydrate hydroxy groups by using aminosugar models
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Methyl amino-deoxy-glycosides with α- and β-gluco, α-galacto, or α-manno stereochemistry with the amino functionality in each of the four possible non-anomeric positions have been synthesized and their pKa values determined by titration. These
- Pedersen, Christian M.,Olsen, Jacob,Brka, Azra B.,Bols, Mikael
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scheme or table
p. 7080 - 7086
(2011/07/08)
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- NOVEL USES OF D-MANNOPYRANOSE DERIVATIVES ACTIVATING ANGIOGENESIS
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The invention relates to the use of certain derivatives of D-mannopyranoside for controlling angiogenesis. These compounds have a pro-angiogenic activity, and can particularly be used for preparing a pharmaceutical composition for treating cardiovascular diseases or for treating muscular atrophy. The invention also relates to certain D-mannopyranoside derivatives, to a pharmaceutical or cosmetic composition containing said derivatives, and to the use of such a cosmetic composition for preventing and/or treating hair loss.
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- Chemoenzymatic synthesis of GDP-azidodeoxymannoses: Non-radioactive probes for mannosyltransferase activity
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GDP-2-, 3-, 4- or 6-azidomannoses can be successfully prepared from the corresponding azidomannose-1-phosphates and GTP using the enzyme GDP-Mannosepyrophosphorylase (GDP-ManPP) from Salmonella enterica and may serve as useful probes for mannosyltransferase activity. The Royal Society of Chemistry.
- Marchesan, Silvia,Macmillan, Derek
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supporting information; experimental part
p. 4321 - 4323
(2009/03/12)
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- Anti-(retro)viral conjugates of saccharides and acetamidino or guanidino compounds
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Conjugates of a saccharide and an acetamidino- or guanidino-compound, of the formula: wherein A is CH3or NH2; X is a linear or branched C1-C8alkyl chain optionally containing hydroxy, amino and/or oxo groups; n is an integer from 1 to 6, and Sac is the residue of a mono-or oligo-saccharide, provided that when A is NH2and X is -(CH2)3—CH(NH2)—C(=O)-, the monosaccharide residue is not substituted at the position 1, and n is an integer from 2 to 6 when Sac is the residue of an oligosaccharide, are useful as antiviral, particularly as antiretroviral, agents, and can be used either alone or together with other compounds used in AIDS treatment such as AZT and/or protease inhibitors, for the treatment of HIV-infection, AIDS and manifestations of AIDS such as Kaposi sarcoma. Particularly preferred compounds are aminoglycoside-arginine conjugates in which the saccharide is a natural aminoglycoside antibiotic such as kanamycin, gentamycin and neomycin that is conjugated to arginine residues.
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Page/Page column 12-13; 37
(2010/01/31)
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- Synthesis and cytotoxicities of mannose conjugated S-Nitroso-N-acetylpenicillamine (SNAP)
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A series of mannose conjugated S-nitroso-N-acetylpenicillamines (SNAPs) has been synthesized, and their cytotoxicities were assessed for DU 145 human prostate cancer cells and Hela R cancer cells.
- Wu, Xuejun,Tang, Xiaoping,Xian, Ming,Brauschweiger, Paul G.,Wang, Peng George
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p. 2303 - 2307
(2007/10/03)
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- Multivalent ligands for the mannose-specific lectin on type 1 fimbriae of Escherichia coli: Syntheses and testing of trivalent α-D-mannoside clusters
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The syntheses of the triantennary cluster α-D-mannosides 16, 19, 23 and 24 and their capacities to inhibit mannose-dependent binding of E. coli HB 101 (pPK14) are described. The cluster glycosides are formed by glycosylation of tris-(3-hydroxypropyl)nitro
- Koetter, Sven,Krallmann-Wenzel, Ulrike,Ehlers, Stefan,Lindhorst, Thisbe K.
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p. 2193 - 2200
(2007/10/03)
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- Enzymes in Oligosaccharide Synthesis: Active-Domain Overproduction, Specificity Study, and Synthetic Use of an α-1,2-Mannosyltransferase with Regeneration of GDP-Man
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The catalytic domain of a membrane-bound α-1,2-mannosyltransferase (ManT) from yeast has been overexpressed in E.coli, at a level of approximately 0.7-0.8 units per L with a specific activity of about 1 U/mg (based on α-methylmannoside) after purification
- Wang, Peng,Shen, Gwo-Jenn,Wang, Yi-Fong,Ichikawa, Yoshitaka,Wong, Chi-Huey
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p. 3985 - 3990
(2007/10/02)
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- An imino-linked carba-disaccharide α-D-mannosidase inhibitor
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In connection with a project concerned with inhibition of the biosynthesis of glycosyl phophatidylinositol (GPI) anchors, we had occasion to synthesise the unsaturated (1→6)-imino-linked carba-disaccharide 2 having the `A-manno' configuration, which was a
- Cottaz,Brimacombe,Ferguson
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p. 341 - 345
(2007/10/02)
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- 6-AMINO-6-DEOXYHEXONOLACTAMS
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6-Azido-6-deoxy-D-mannose (III), prepared from methyl 4,6-O-benzylidene-α-D-mannopyranoside, 6-azido-6-deoxy-D-talose (XI), prepared from methyl 6-azido-2,3-O-isopropylidene-α-D-mennopyranoside (VII) via 4-keto derivative VIII, and 6-azido-6-deoxy-L-idose (XVIII), obtained from 5,6-anhydro-1,2-O-isopropylidene-β-L-idofuranose, on oxidation with bromine and subsequent reduction of the azido group afforded the corresponding 6-amino-6-deoxyhexonolactams V, XV, and XXI. 6-Amino-6-deoxyhexonic acids IV and XIV were also prepared.
- Kefurt, Karel,Kefurtova, Zdenka,Jary, Jiri
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p. 1795 - 1805
(2007/10/02)
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- Fluorinated Carbohydrates. 2. Selective Fluorination of Gluco- and Mannopyranosides. Use of 2-D NMR for Structural Assignments
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Methyl and phenyl α-glucosides, or suitably protected derivatives, may be selectively fluorinated with (diethylamino)sulfur trifluoride (DAST) at the 4- or 6-position to afford the corresponding fluorinated galacto- or glucopyranoside.In contrast to the α-glucosides, the β-glucosides underwent ring fluorination at C-3 to give the 3-deoxy-3-fluoro-β-allo derivatives.High yields of primary fluorinated (C-6) products were obtained from both α- and β glucosides by use of appropriate reaction times.Use of 6-O-trityl derivatives of methyl α- and β-glucosides gave methyl 4-deoxy-4-fluoro-α-galactopyranoside (22) and methyl 3-deoxy-3-fluoro-β-allopyranoside (19), respectively.Use of 2-D NMR (COSY) for structural assignements is also described.Fluorinated p-nitrophenyl α- and β-gluco- and -galactopyranosides (such as 15) have also been prepared by the above DAST reactions. 6-O-Pivaloate esters of methyl α-gluco-and α- and β-galactopyranoside have been prepared as an acid and DAST-stable 6-O protecting group.Proof of an intramolecular fluoride-ion delivery mechanism for the SN2 displacement reaction at C-4 in methyl α-D-mannopyranoside is described.Methyl 4-amino-4,6-dideoxy-6-fluoro-α-D-glucopyranoside, methyl 6-amino-3,6-dideoxy-3-fluoro-β-D-allopyranoside, and methyl 6-amino-4,6-dideoxy-4-fluoro-α-D-talopyranoside were also prepared via the above methodology.
- Card, Peter J.,Reddy, Gade S.
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p. 4734 - 4743
(2007/10/02)
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