NMR Spectroscopy of supramolecular chemistry on protein surfaces

• Peter Bayer,
• Anja Matena and
• Christine Beuck

Beilstein J. Org. Chem. 2020, 16, 2505–2522, doi:10.3762/bjoc.16.203

• combination of two or more GCP moieties with variable linkers enables the construction of multivalent ligands geared towards a specific spot on protein surface, which by design can lead to either stabilization [42][43][44][45] or inhibition [46] of a given protein–protein interaction. The inhibition of the

• multivalent ligands, like multi-armed GCP ligands with flexible scaffolds or nanoparticles, have been published yet. NMR spectroscopy is the ideal method to gain structural information and identify residues involved in ligand binding because it delivers single-residue resolution. It is also suitable to

Host–guest interactions between p-sulfonatocalix[4]arene and p-sulfonatothiacalix[4]arene and group IA, IIA and f-block metal cations: a DFT/SMD study

• Valya K. Nikolova,
• Cristina V. Kirkova,
• Silvia E. Angelova and
• Todor M. Dudev

Beilstein J. Org. Chem. 2019, 15, 1321–1330, doi:10.3762/bjoc.15.131

• are not as good as those of other common macrocycles. Two positions (phenolic OH groups and p-positions) in the calixarenes’ structure can be easily modified by subsequent reactions [4]. As a result, calixarenes have a great potential as simple scaffolds to build molecular receptors and multivalent

• ligands with novel features. They have found various applications in chemical [5], analytical [6][7][8][9], and engineering materials fields (self-assembling monolayers, surfactants, sensors [10][11]), in polymer synthesis [12][13], controlled drug-delivery systems [14], and so on, besides the biochemical

Lectins of Mycobacterium tuberculosis – rarely studied proteins

• Katharina Kolbe,
• Sri Kumar Veleti,
• Norbert Reiling and
• Thisbe K. Lindhorst

Beilstein J. Org. Chem. 2019, 15, 1–15, doi:10.3762/bjoc.15.1

• homodimers, homotrimers, and higher-ordered oligomers, which increases their avidity for multivalent ligands. C-Type lectins play key roles in cell–cell interactions, such as host–pathogen interactions, and phagocytosis [92]. The Mtb gene product of Rv2075c shows partial amino acid sequence similarity to

An overview of recent advances in duplex DNA recognition by small molecules

• Sayantan Bhaduri,
• Nihar Ranjan and
• Dev P. Arya

Beilstein J. Org. Chem. 2018, 14, 1051–1086, doi:10.3762/bjoc.14.93

• are reports of natural and designed molecules that display multivalency in DNA recognition by binding at more than recognition sites (minor groove, major groove or base pair insertion) [11][12][13]. In synthetic multivalent ligands, which are made to enhance DNA affinity, tether length and composition

• especially the multivalent ligands that can simultaneously recognize one or more sites on DNA leading to strong affinity for DNA. We finally shed light on new reports of DNA alkylating agents towards the end of this review. While it is impossible to absorb the vast expanse and comprehensiveness of reports on

Carbohydrate inhibitors of cholera toxin

• Vajinder Kumar and
• W. Bruce Turnbull

Beilstein J. Org. Chem. 2018, 14, 484–498, doi:10.3762/bjoc.14.34

• been drawn for the receptor binding to AB5 toxins; while some target on the individual binding sites, others are intended at designing multivalent ligands against the entire toxin B pentamer [6][30][31]. Monovalent receptor-binding inhibitors Bernardi and co-workers designed carbohydrate derivatives

• weakly binding) monovalent inhibitors [30][31]. Multivalent ligands have been long applied to a wide range of protein targets [43][44][45]. By having an inhibitor that may bind simultaneously with multiple binding sites, the dissociation rate of the complex is effectively reduced. Even if any individual

• gain in inhibitory potency for the multivalent ligands can be in many orders of magnitude. Here we have divided multivalent ligands and inhibitors of cholera toxin into three classes: sub-pentavalent inhibitors; pentavalent inhibitors; and inhibitors containing more than five ligands. Sub-pentavalent

Peptide–polymer ligands for a tandem WW-domain, an adaptive multivalent protein–protein interaction: lessons on the thermodynamic fitness of flexible ligands

• Katharina Koschek,
• Vedat Durmaz,
• Oxana Krylova,
• Marek Wieczorek,
• Shilpi Gupta,
• Martin Richter,
• Alexander Bujotzek,
• Christina Fischer,
• Rainer Haag,
• Christian Freund,
• Marcus Weber and
• Jörg Rademann

Beilstein J. Org. Chem. 2015, 11, 837–847, doi:10.3762/bjoc.11.93

• Informationstechnik Berlin, Numerical Analysis and Modelling, Takustr. 7, 14195 Berlin, Germany 10.3762/bjoc.11.93 Abstract Three polymers, poly(N-(2-hydroxypropyl)methacrylamide) (pHPMA), hyperbranched polyglycerol (hPG), and dextran were investigated as carriers for multivalent ligands targeting the adaptive

• determine the binding affinity, the enthalpic and entropic contributions to free binding energy, and the stoichiometry of binding for all peptide–polymer conjugates. Binding affinities of all multivalent ligands were in the µM range, strongly amplified compared to the monovalent ligand P1 with a KD > 1 mM

• degree of freedom to move in the plane of the membrane, or by incorporation into dynamic multiprotein complexes. Design of potent multivalent ligands for flexible receptor arrangements is a considerable challenge, as the flexibility of multivalent ligands and the flexibility of receptors have to be

Influence of length and flexibility of spacers on the binding affinity of divalent ligands

• Susanne Liese and
• Roland R. Netz

Beilstein J. Org. Chem. 2015, 11, 804–816, doi:10.3762/bjoc.11.90

• ]. Also in drug design, the synthesis of artificial multivalent ligands is a promising route to increase the binding affinity or to reduce the amount of substance required for treatment [4][5][6][7]. The term multivalency is used for systems that consist of several identical binding partners. Thereby, the

• multivalent dissociation constant, in the limit of low receptor concentrations, i.e., for [R]0 << Kmulti: To compare monovalent and multivalent ligands we use the relative binding affinity (RBA), which we define as Here, the factor 2 accounts for the valency of the ligand and ensures that the concentration of

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

• multivalent ligands displaying multiple copies of recognition elements are a logical tool to study mechanisms of galectin-1 mediated biological activities. Mutivalent frameworks have been used to organize lectins and to mediate biological activity for the advancement of mechanistic understandings [22][23][24

• ][25]. Synthetic multivalent ligands have been observed to enhance galectin-1 binding through the glycoside cluster effect by mediating the formation of cross-linked aggregates [26][27][28]. Tinari et al. observed galectin-1 augmentation of homotypic cellular aggregation in human melanoma cells (A375

• et al. designed self-assembled pseudopolyrotaxanes as a flexible and adaptable multivalent neoglycoconjugate for galectin-1 [31]. Using this multivalent supramolcular architecture, galectin-1 was observed to bind to flexible multivalent ligands with higher affinity than could be achieved using less

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

• 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

• a social self-sorting manner as outlined in Scheme 2. The basic idea is to design multivalent ligands that do not show a (high) tendency to form discrete oligonuclear homoleptic aggregates but rather form metallosupramolecular polymeric structures when mixed with suitable metal ions. In such a

• the maximum occupancy rule [24] is obeyed which open-chain oligomeric or polymeric species do not do. Results and Discussion Design and synthesis Our strategy asks for the design of rigid multivalent ligands that present their metal binding sites in a way that the formation of discrete macrocyclic or

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

• . To our knowledge these are the first examples of the use of BODIPY or pyrene as a scaffold to display multivalent ligands. Although the trivalent BODIPY-derived DNJ clusters are water soluble, a co-solvent is necessary to dissolve the tetravalent pyrene-derived DNJ clusters in water. Photophysical

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

• -acetyllactosamine was also evaluated. Results and Discussion As part of our project on the synthesis and biological evaluation of multivalent ligands, two families of mono- and divalent structures were synthesized in order to study their ability as acceptors or inhibitors of the reaction catalyzed by the T. cruzi

• report on the inhibition properties of multivalent ligands on the TcTS [31]. It should be noted that by using SL as donor substrate and quantifying the new sialylated compounds we assess that only the trans-sialidase activity is measured, and not an alternative sialidase activity. Only traces of free

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

• mind to develop simpler, lower molecular weight, and hydrosoluble multivalent ligands against lecA and lecB, able to exert useful biofilm inhibition and to provide useful tools for investigating the roles of lecA and lecB in the colonization process. Our investigations further aimed at concentrating a

Clicked and long spaced galactosyl- and lactosylcalix[4]arenes: new multivalent galectin-3 ligands

• Silvia Bernardi,
• Paola Fezzardi,
• Gabriele Rispoli,
• Stefania E. Sestito,
• Francesco Peri,
• Francesco Sansone and
• Alessandro Casnati

Beilstein J. Org. Chem. 2014, 10, 1672–1680, doi:10.3762/bjoc.10.175

• efficient multivalent ligands for a series of pathological lectins. For instance, cholera toxin is bound rather efficiently by calix[4]arene [16] and calix[5]arene [17] derivatives, while examples of Pseudomonas aeruginosa LecB binding were reported with galactosylcalixarenes blocked in different

High-affinity multivalent wheat germ agglutinin ligands by one-pot click reaction

• Henning S. G. Beckmann,
• Heiko M. Möller and
• Valentin Wittmann

Beilstein J. Org. Chem. 2012, 8, 819–826, doi:10.3762/bjoc.8.91

• enhancements of the multivalent ligands with their ability to bind to the protein in a chelating mode. The best WGA ligand is a trivalent cluster with an IC50 value of 220 nM. Calculated per mol of contained chitobiose, this is the best WGA ligand known so far. Keywords: carbohydrates; click chemistry

• multivalent ligands with disproportionally enhanced avidity. A prerequisite for an effective multivalency effect, however, is that the linking spacer between the individual epitopes has the correct geometry to allow a simultaneous multipoint association, i.e., a chelating binding mode. Wheat germ agglutinin

• (WGA), besides other plant lectins such as Con A, has been intensively employed as a model lectin to study the influence of the structure of multivalent ligands on the binding affinity. WGA ligands of defined structure containing two to twelve GlcNAc residues obtained either by individual synthesis [28

Synthetic glycopeptides and glycoproteins with applications in biological research

• Ulrika Westerlind

Beilstein J. Org. Chem. 2012, 8, 804–818, doi:10.3762/bjoc.8.90

• tyrosine residues form the “tyrosine gate” [134]. By π–π stacking interactions with the aromatic tyrosine residues, monovalent α-mannose ligands containing hydrophobic aglycons, have shown increased binding affinities [128][135][136]. Employing multivalent ligands, the binding affinity to FimH could be

A bivalent glycopeptide to target two putative carbohydrate binding sites on FimH

• Thisbe K. Lindhorst,
• Kathrin Bruegge,
• Andreas Fuchs and
• Oliver Sperling

Beilstein J. Org. Chem. 2010, 6, 801–809, doi:10.3762/bjoc.6.90

• 1 fimbriae with a monovalent carbohydrate recognition domain (CRD) that is known from X-ray studies. However, binding studies with multivalent ligands have suggested an additional carbohydrate-binding site on this protein. In order to prove this hypothesis, a bivalent glycopeptide ligand with the

• light of very recent findings, our observations as well as results with other multivalent ligands, might be well explained by an allosteric model of FimH-mediated adhesion [35]. It has been reported that interdomain allosteric regulation can lead to a catch bond mechanism of adhesion in which the

• pocket. This leads to a low-affinity state of the protein, whereas upon interaction with mannose, the domains separate and the binding domain untwists and elongates into a tight mannose-binding pocket. It will be important to investigate, how complex multivalent ligands function in this allosteric