Orthogonal dual-modification of proteins for the engineering of multivalent protein scaffolds

• Michaela Mühlberg,
• Michael G. Hoesl,
• Christian Kuehne,
• Jens Dernedde,
• Nediljko Budisa and
• Christian P. R. Hackenberger

Beilstein J. Org. Chem. 2015, 11, 784–791, doi:10.3762/bjoc.11.88

• Berlin, Institut für Organische und Bioorganische Chemie, Institut für Chemie, Brook-Taylor-Str. 2, 12489 Berlin, Germany 10.3762/bjoc.11.88 Abstract To add new tools to the repertoire of protein-based multivalent scaffold design, we have developed a novel dual-labeling strategy for proteins that

• the generation of nanostructured scaffolds with precisely defined dimensions and configurations [7][8][9][10][11][12]. We have recently contributed to this field using globular proteins as multivalent scaffolds for the structurally-defined presentation of ligands. In a proof-of-principle study to

• engineer multivalent glycoprotein conjugates, we have used the incorporation of non-canonical amino acids (NCAA) [13] by supplementation based incorporation (SPI) [14][15][16][17] in auxotroph expression systems followed by the chemoselective Cu-catalyzed azide–alkyne cycloaddition (CuAAC) to attach

Regulation of integrin and growth factor signaling in biomaterials for osteodifferentiation

• Qiang Wei,
• Theresa L. M. Pohl,
• Anja Seckinger,
• Joachim P. Spatz and
• Elisabetta A. Cavalcanti-Adam

Beilstein J. Org. Chem. 2015, 11, 773–783, doi:10.3762/bjoc.11.87

• factors to induce osteogenic differentiation of stem cells, and discuss the signaling pathways that are initiated by both individual and cooperative parameters. The joint effect of integrin ligands and growth factors is highlighted as the multivalent interactions for bone therapy. Keywords: biomaterials

Discrete multiporphyrin pseudorotaxane assemblies from di- and tetravalent porphyrin building blocks

• Mirko Lohse,
• Larissa K. S. von Krbek,
• Sebastian Radunz,
• Suresh Moorthy,
• Christoph A. Schalley and
• Stefan Hecht

Beilstein J. Org. Chem. 2015, 11, 748–762, doi:10.3762/bjoc.11.85

• ] to life science [13][14][15][16][17] have benefited from the development of the basic concepts of molecular recognition, templation [18], self-assembly [19], or self-sorting [20][21], just to name a few. More recently, multivalent binding [22][23][24] and cooperativity [25][26] have attracted

• only contributes to binding enhancement, but also helps to exert control over complex formation. For example, “molecular elevators” have been constructed by Stoddart et al. [30][31] and giant porphyrin wheels were prepared by Anderson and co-workers [32][33], both using a multivalent template strategy

• -8 C1 as well as of C2 and C4 with monovalent dibenzylammonium A1 (Figure 2, top), followed by the results obtained for the multivalent 1:1 and 2:1 complexes A2@C2, A22@C4, A4@C22 and A4@C4 (Figure 2, bottom). [3]- and [5]pseudorotaxanes from monovalent building blocks First the association of A2 and

Glycodendrimers: tools to explore multivalent galectin-1 interactions

• Jonathan M. Cousin and
• Mary J. Cloninger

Beilstein J. Org. Chem. 2015, 11, 739–747, doi:10.3762/bjoc.11.84

• Jonathan M. Cousin Mary J. Cloninger Department of Chemistry and Biochemistry, Montana State University, Bozeman, MT 59717, USA 10.3762/bjoc.11.84 Abstract Four generations of lactose-functionalized polyamidoamine (PAMAM) were employed to further the understanding of multivalent galectin-1

• mediated interactions. Dynamic light scattering and fluorescence microscopy were used to study the multivalent interaction of galectin-1 with the glycodendrimers in solution, and glycodendrimers were observed to organize galectin-1 into nanoparticles. In the presence of a large excess of galectin-1

• glycodendrimers provided competitive binding sites for galectin-1, which diverted galectin-1 from its typical function in cellular aggregation of DU145 cells. Keywords: dendrimer; galectin-1; glycodendrimer; multivalent; nanoparticle; Introduction Galectin-1 is a multivalent protein that mediates biological

Multivalent polyglycerol supported imidazolidin-4-one organocatalysts for enantioselective Friedel–Crafts alkylations

• Tommaso Pecchioli,
• Manoj Kumar Muthyala,
• Rainer Haag and
• Mathias Christmann

Beilstein J. Org. Chem. 2015, 11, 730–738, doi:10.3762/bjoc.11.83

• described. A modified tyrosine-based imidazolidin-4-one was grafted to a soluble high-loading hyperbranched polyglycerol via a copper-catalyzed alkyne–azide cycloaddition (CuAAC) reaction and readily purified by dialysis. The efficiency of differently functionalized multivalent organocatalysts 4a–c was

• ; multivalency; Introduction In nature, multivalent architectures, e.g., enzymes, bacteria or viruses, are responsible for cooperative interactions between different interfaces or molecules [1]. The realization of the concept of multivalency has attracted attention from different fields ranging from medicine

• and biochemistry [2] to supramolecular chemistry [3][4] and materials sciences [5]. However, applications in catalysis are still limited [6][7][8]. Recently, the use of polymeric support has stimulated the development of multivalent architectures for catalytic applications [9]. In general, both linear

Probing multivalency in ligand–receptor-mediated adhesion of soft, biomimetic interfaces

• Stephan Schmidt,
• Hanqing Wang,
• Daniel Pussak,
• Simone Mosca and
• Laura Hartmann

Beilstein J. Org. Chem. 2015, 11, 720–729, doi:10.3762/bjoc.11.82

• a concanavalin A (ConA) layer via poly(ethylene glycol)-(PEG)-based soft colloidal probes (SCPs). Special emphasis is on the dependence of multivalent presentation and density of carbohydrate units on specific adhesion. Consequently, we first present a synthetic strategy that allows for controlled

• type. Remarkably, the results indicated the absence of a molecular-level enhancement of mannose/ConA interaction due to chelate- or subsite-binding. The results seem to support the fact that weak carbohydrate interactions at mechanically flexible interfaces hardly undergo multivalent binding but are

• glycocalyx interacts also with surface anchored membrane receptors. Thus, the interactions between these surfaces are again multivalent interactions, just on a larger scale between two surfaces. Such carbohydrate based multivalent surface–surface interactions represent a large range of crucial biological

DNA display of glycoconjugates to emulate oligomeric interactions of glycans

• Alexandre Novoa and
• Nicolas Winssinger

Beilstein J. Org. Chem. 2015, 11, 707–719, doi:10.3762/bjoc.11.81

• therapeutic applications. We hope that the examples presented in this review will encourage researchers in glycoscience to embrace and further develop the use of glycan display by programmed assemblies. DNA display of glycans. Multivalent triangular glycoDNA assemblies. DNA display of PNA-tagged glycans

• designed to emulate HIV's gp120 epitope. Combinatorial assembly and selection of two PNA glycoconjugate libraries on DNA templates. DNA display of ligand bridging opposing binding sites in a lectin (ECL). A glycan array prepared by hybridization of glycan–DNA conjugates and screening of RCA120. Multivalent

Exploring monovalent and multivalent peptides for the inhibition of FBP21-tWW

• Lisa Maria Henning,
• Sumati Bhatia,
• Miriam Bertazzon,
• Michaela Marczynke,
• Oliver Seitz,
• Rudolf Volkmer,
• Rainer Haag and
• Christian Freund

Beilstein J. Org. Chem. 2015, 11, 701–706, doi:10.3762/bjoc.11.80

• -Universitätsmedizin Berlin, Berlin, Germany 10.3762/bjoc.11.80 Abstract The coupling of peptides to polyglycerol carriers represents an important route towards the multivalent display of protein ligands. In particular, the inhibition of low affinity intracellular protein–protein interactions can be addressed by this

• individual WW domains and with a KD of 150 μM to the tandem-WW1–WW2 construct. Secondly, this sequence was coupled to a hyperbranched polyglycerol (hPG) that allowed for the multivalent display on the surface of the dendritic polymer. This novel multifunctional hPG-peptide conjugate displayed a KD of 17.6 µM

• which demonstrates that the new carrier provides a venue for the future inhibition of proline-rich sequence recognition by FBP21 during assembly of the spliceosome. Keywords: FBP21-tWW; isothermal titration calorimetry; multivalent polymers; polyglycerol peptide conjugates; proline-rich sequence

Self-assembly of heteroleptic dinuclear metallosupramolecular kites from multivalent ligands via social self-sorting

• Christian Benkhäuser and
• Arne Lützen

Beilstein J. Org. Chem. 2015, 11, 693–700, doi:10.3762/bjoc.11.79

• central 1,3-diethynylbenzene unit 2 were synthesized. Each of these ligands acts as a multivalent entity for the binding of two copper(I) ions. Upon coordination to the metal ions these two ligands undergo selective self-assembly into heteroleptic dinuclear metallosupramolecular kites in a high-fidelity

• attractive since they allow access to much more complex supramolecular architectures than homoleptic systems do. Unfortunately, the selective formation of heteroleptic complexes from a mixture of different multivalent ligands bridging two or more metal ions is more challenging and there is only a limited

• of metallosupramolecular aggregates from multivalent rigid concave ligand structures through (chiral) self-sorting processes [16][17][18][19][20][21][22][23], we were wondering whether we could yet establish another approach to achieve the formation of heteroleptic metallosupramolecular assemblies in

First principle investigation of the linker length effects on the thermodynamics of divalent pseudorotaxanes

• Andreas J. Achazi,
• Doreen Mollenhauer and
• Beate Paulus

Beilstein J. Org. Chem. 2015, 11, 687–692, doi:10.3762/bjoc.11.78

• hindrance. These investigations proved that besides the primary binding sites in multivalent arrangements the interaction of the linkers can influence the binding process significantly. Therefore the term of non-innocent linkers introduced in [16] is well justified. Structures of the mono- and divalent

Synthesis of tripodal catecholates and their immobilization on zinc oxide nanoparticles

• Franziska Klitsche,
• Julian Ramcke,
• Julia Migenda,
• Andreas Hensel,
• Tobias Vossmeyer,
• Horst Weller,
• Silvia Gross and
• Wolfgang Maison

Beilstein J. Org. Chem. 2015, 11, 678–686, doi:10.3762/bjoc.11.77

• anchor groups for biomedically relevant metal surfaces and nanoparticles. We report here the synthesis of new tripodal catecholates as multivalent anchor molecules for immobilization on metal surfaces and nanoparticles. The tripodal catecholates have been conjugated to various effector molecules such as

• consequence of reversible binding at neutral and slightly acidic pH. Multivalent catecholates, such as MAPs or oligo-DOPA, overcome this drawback of simple catecholate derivatives and show increased binding affinities to metal surfaces. They are therefore attractive anchors for durable immobilizations on

• of new tripodal catecholates as valuable multivalent anchor molecules for immobilization on metal surfaces and nanoparticles. These catecholate anchors make use of a biomimetic covalent immobilization concept as found for example in mussel adhesion proteins. Our tripodal catecholate anchors are

Synthesis of carbohydrate-scaffolded thymine glycoconjugates to organize multivalency

• Anna K. Ciuk and
• Thisbe K. Lindhorst

Beilstein J. Org. Chem. 2015, 11, 668–674, doi:10.3762/bjoc.11.75

• on the cell surface. Thus many synthetic multivalent glycoconjugates have been developed as important tools for glycobiological research. We are expanding this collection of molecules by the introduction of carbohydrate-scaffolded divalent glycothymine derivatives that can be intramolecularily

• other way. These processes allow to control, regulate and fine-tune the complex life of eukaryotes. We have recently focused our research dedicated to multivalency effects in carbohydrate recognition on the aspect of conformational control of multivalent assemblies, such as micelles [5] or glycoarrays

• for eventual immobilisation of the final thymine glycoconjugate on a surface or for conjugation to another multivalent compound. For the click reaction of 5 with the thymine derivative 6, copper sulfate and sodium ascorbate were used. The conjugation product 7 was obtained in 71% yield and showed good

Design, synthesis and photochemical properties of the first examples of iminosugar clusters based on fluorescent cores

• Mathieu L. Lepage,
• Antoine Mirloup,
• Manon Ripoll,
• Fabien Stauffert,
• Anne Bodlenner,
• Raymond Ziessel and
• Philippe Compain

Beilstein J. Org. Chem. 2015, 11, 659–667, doi:10.3762/bjoc.11.74

• ), the first oral treatment for Gaucher and Niemann–Pick diseases (Figure 1) [1][6][7][8]. Despite their high therapeutic potential, the extensive studies in the field and the myriad of compounds synthesized, very few examples of multivalent iminosugars were reported in the literature until recently [9

• ][10]. From 2010, the field has however experienced a major take-off with the discovery of the first strong multivalent effects in glycosidase inhibition observed with DNJ clusters based on β-cyclodextrin or C60 cores showing strong affinity enhancements over the corresponding monomers (up to 610-fold

• per DNJ unit) [11][12]. In the following years, an impressive ever-growing number of multivalent iminosugars based on various scaffolds, ligands and linkers have been synthesized to further investigate the impact of multivalency on glycosidase inhibition [9][10][11][12][13][14][15][16][17][18][19][20

Synthesis of multivalent carbohydrate mimetics with aminopolyol end groups and their evaluation as L-selectin inhibitors

• Joana Salta,
• Jens Dernedde and
• Hans-Ulrich Reissig

Beilstein J. Org. Chem. 2015, 11, 638–646, doi:10.3762/bjoc.11.72

• since in the literature similar conditions were found for the synthesis of multivalent acetyl-protected carbohydrates [29]. As possible explanation we assume that the formation of product 6 is sterically too hindered due to the bulkiness of the TBS-protecting groups of 3 and the short distance between

• excellent yields. As previously mentioned, an additional goal of this study was the investigation of multivalent compounds starting from the simple aminopolyol 2. Analogously to aminopyran 1, the hydroxy groups of 2 were first protected with TBS groups under standard conditions to furnish compound 16. To be

• the fully deprotected divalent amides 21–23 were isolated in an operationally very simple manner and in excellent yields (Table 2). In order to directly obtain the unprotected multivalent carbohydrate mimetics we looked for alternative methods not requiring the protection of the hydroxy groups of 1 or

Potential of acylated peptides to target the influenza A virus

• Daniel Lauster,
• Damian Pawolski,
• Julian Storm,
• Kai Ludwig,
• Rudolf Volkmer,
• Henry Memczak,
• Andreas Herrmann and
• Sumati Bhatia

Beilstein J. Org. Chem. 2015, 11, 589–595, doi:10.3762/bjoc.11.65

• , Germany 10.3762/bjoc.11.65 Abstract For antiviral drug design, especially in the field of influenza virus research, potent multivalent inhibitors raise high expectations for combating epidemics and pandemics. Among a large variety of covalent and non-covalent scaffold systems for a multivalent display of

• inhibitors, we created a simple supramolecular platform to enhance the antiviral effect of our recently developed antiviral Peptide B (PeBGF), preventing binding of influenza virus to the host cell. By conjugating the peptide with stearic acid to create a higher-order structure with a multivalent display, we

• protein M2 (amantadine, rimantadine) are available. However, the efficiencies of these drugs are competing with fast and continuously changing phenotypes of the influenza virus [2]. Among different strategies to block virus entry [3], several multivalent inhibitors preventing binding of the influenza

Synthesis and surface grafting of a β-cyclodextrin dimer facilitating cooperative inclusion of 2,6-ANS

• Lars W. Städe,
• Thorbjørn T. Nielsen,
• Laurent Duroux,
• Reinhard Wimmer,
• Kyoko Shimizu and
• Kim L. Larsen

Beilstein J. Org. Chem. 2015, 11, 514–523, doi:10.3762/bjoc.11.58

• spectroscopy and microscopy. Numerous methods have already been reported for the functionalization of planar silicon dioxide surfaces with monomeric β-CD for supramolecular inclusion of appropriate guest molecules [14]. Further, it has been demonstrated that such surfaces may serve as a multivalent receptor

Synthesis of divalent ligands of β-thio- and β-N-galactopyranosides and related lactosides and their evaluation as substrates and inhibitors of Trypanosoma cruzi trans-sialidase

• María Emilia Cano,
• Rosalía Agusti,
• Alejandro J. Cagnoni,
• María Florencia Tesoriero,
• José Kovensky,
• María Laura Uhrig and
• Rosa M. de Lederkremer

Beilstein J. Org. Chem. 2014, 10, 3073–3086, doi:10.3762/bjoc.10.324

• . Keywords: β-galactopyranosides; multivalent ligands; sialic acid; sugar scaffolds; T. cruzi trans-sialidase; Introduction Trypanosoma cruzi, the agent of American trypanosomiasis, affects millions of people in Latin America [1][2] and is transmitted to animals, including humans, by triatomine insects. The

• , lactitol efficiently controlled the apoptosis triggered by TcTS [23]. The synthesis of multivalent glycoclusters designed to be high affinity ligands for specific proteins has been an active area of research during the last years [24][25][26][27][28]. Among them, tetravalent glycoclusters bearing β

• [32][33]. In the present work, we selected thioglycosidic and N-glycosidic bonds to link the acceptor sugars to a platform by click chemistry, taking into consideration that they are highly resistant to enzymatic hydrolysis [34][35]. We have previously described the synthesis of multivalent β

Towards the sequence-specific multivalent molecular recognition of cyclodextrin oligomers

• Michael Kurlemann and
• Bart Jan Ravoo

Beilstein J. Org. Chem. 2014, 10, 2428–2440, doi:10.3762/bjoc.10.253

• Michael Kurlemann Bart Jan Ravoo Organic Chemistry Institute, Westfälische Wilhelms-Universität Münster, Corrensstrasse 40, 48149 Münster, Germany 10.3762/bjoc.10.253 Abstract Sequence-specific multivalent molecular recognition has been recognized to play a major role in biological processes

• -covalent interactions stable yet reversible systems are generated, which are responsive to external stimuli. These advantages have made synthetic multivalent systems interesting for a broad field of applications. In the case of medicinal applications multivalent molecules have been used as inhibitors of

• toxins or viruses and for imaging and targeted drug delivery [3]. Hydrogels which are built up by multivalent host–guest interactions and vesicles of amphiphilic host molecules have been intensively studied for their ability to function as drug delivery systems as well [4][5][6][7][8][9]. Additionally

Synthesis and immunological evaluation of protein conjugates of Neisseria meningitidis X capsular polysaccharide fragments

• Laura Morelli,
• Damiano Cancogni,
• Marta Tontini,
• Alberto Nilo,
• Sara Filippini,
• Paolo Costantino,
• Maria Rosaria Romano,
• Francesco Berti,
• Roberto Adamo and
• Luigi Lay

Beilstein J. Org. Chem. 2014, 10, 2367–2376, doi:10.3762/bjoc.10.247

• the native polymer and conjugated to the same protein. This finding suggests that oligomers longer than three repeating units are possibly needed to mimic the activity of the native polysaccharide. Keywords: carbohydrates; glycoconjugates; immunology; multivalent glycosystems Neisseria meningitidis

Multivalent glycosystems for nanoscience

• Thisbe K. Lindhorst

Beilstein J. Org. Chem. 2014, 10, 2345–2347, doi:10.3762/bjoc.10.244

• Thisbe K. Lindhorst Otto Diels Institute of Organic Chemistry, Christiana Albertina University of Kiel, Otto-Hahn-Platz 3/4, 24098 Kiel, Germany 10.3762/bjoc.10.244 Keywords: multivalent glycosystems; Carbohydrates constitute the most abundant class of biomolecules on Earth. They are “global

• the field of glycosciences. This enterprise has focused its research on the potential applications and social benefits that lie in the field. For instance, multivalent glycoconjugates can be used as anti-adhesive drugs against microbial infections. They could be developed into bioimaging agents that

• can target specific tissues. Indeed, they will certainly find applications in materials science and in medicine, for example, in drug delivery or diagnostics [36]. Consequently, this COST Action (CM1102) [37] was called “MultiGlycoNano” to illustrate that multivalent glycostructures now enter the era

Indium-mediated allylation in carbohydrate synthesis: A short and efficient approach towards higher 2-acetamido-2-deoxy sugars

• Christopher Albler,
• Ralph Hollaus,
• Hanspeter Kählig and
• Walther Schmid

Beilstein J. Org. Chem. 2014, 10, 2230–2234, doi:10.3762/bjoc.10.231

• azide reduction followed by final deacetylation using methanolic sodium methoxide furnishes the title compounds. Keywords: allylation; carbohydrates; epoxidation; indium; multivalent glycosystems; organocatalysis; Introduction The indium-mediated allylation of carbonyl compounds has proven to be a

Expeditive synthesis of trithiotriazine-cored glycoclusters and inhibition of Pseudomonas aeruginosa biofilm formation

• Meriem Smadhi,
• Sophie de Bentzmann,
• Anne Imberty,
• Marc Gingras,
• Raoudha Abderrahim and
• Peter G. Goekjian

Beilstein J. Org. Chem. 2014, 10, 1981–1990, doi:10.3762/bjoc.10.206

• glycoclusters based on a triazine core bearing D-galactose and L-fucose epitopes are able to inhibit biofilm formation by Pseudomonas aeruginosa. These multivalent ligands are simple to synthesize, are highly soluble, and can be either homofunctional or heterofunctional. The galactose-decorated cluster shows

• good affinity for Pseudomonas aeruginosa lectin lecA. They are convenient biological probes for investigating the roles of lecA and lecB in biofilm formation. Keywords: antibiotic; biofilm; glycocluster; lectin; multivalency effect; multivalent glycosystems; Introduction Pseudomonas aeruginosa (PA

• bioactivity of these lectins in host recognition and adhesion in biofilm formation represents an attractive antibacterial strategy, as multivalent carbohydrate motifs on cell surfaces are known to mediate a broad range of cellular and tissue adhesion processes. Carbohydrate recognition in biological systems

Synthesis of rigid p-terphenyl-linked carbohydrate mimetics

• Maja Kandziora and
• Hans-Ulrich Reissig

Beilstein J. Org. Chem. 2014, 10, 1749–1758, doi:10.3762/bjoc.10.182

• mimetics; hydrogenolysis; multivalent glycosystems; 1,2-oxazines; samarium diiodide; Suzuki cross-coupling; Introduction Carbohydrates are the class of biomolecules with the highest structural diversity [1][2]. Specific carbohydrates are responsible for cell-type specific interactions [3] and they are

• conjugates may have even higher binding affinities and specificities than their flexible multivalent equivalents [14][15]. The rigidity of the system is supposed to improve the overall activity of the ligands by overcoming the entropic penalty of flexible multivalent scaffolds [16]. Cross-coupling reactions

• biphenyl-linked dimers were prepared by Lewis acid-catalyzed glycosidations [23]. All these examples possess an acid-labile O-glycosidic bond and are labile to hydrolysis and enzymes. Therefore, new approaches to the synthesis of rigid multivalent C-arylglycosides should be a valuable extension of

Convergent synthetic methodology for the construction of self-adjuvanting lipopeptide vaccines using a novel carbohydrate scaffold

• Vincent Fagan,
• Istvan Toth and
• Pavla Simerska

Beilstein J. Org. Chem. 2014, 10, 1741–1748, doi:10.3762/bjoc.10.181

• by the preparation of a second vaccine candidate which incorporated an additional promiscuous T-helper epitope. Keywords: amino acid lipidation; cycloadditon reaction; multivalent glycosystems; peptide vaccine; tetrapropargyl glucopyranose; Introduction Vaccination is often the most effective and

Bifunctional dendrons for multiple carbohydrate presentation via carbonyl chemistry

• Davide Bini,
• Francesco Nicotra and
• Laura Cipolla

Beilstein J. Org. Chem. 2014, 10, 1686–1691, doi:10.3762/bjoc.10.177

• carbonyl group at the termini has been carried out. The carbonyl group has been exploited for the multivalent conjugation to a sample saccharide by reductive amination and alkoxyamine conjugation. Keywords: bis-MPA; carbohydrates; dendrons; levulinic acid; multivalency; multivalent glycosystems

• understand these phenomena, dendrimers and dendrons have been developed to provide multivalent glycoconjugates [13][14]. Here, we propose the synthesis of novel dendron structures which allow for the multivalent conjugation of carbohydrates via carbonyl chemistry. Results and Discussion The