Low‐Molecular‐Weight Dendrons for DNA Binding and Release by Reduction‐Triggered Degradation of Multivalent Interactions

Losing the grip : The synthesis of multivalent low‐molecular‐weight dendrons with lysine branching units coupled to disulfide‐linked spermine surface groups is described. It is furthermore demonstrated that the dendrons bind DNA with good affinity (see image), but are also able to release the DNA in a reductive environment.

     

Exploring the Limits of Bivalency by DNA‐Based Spatial Screening

Multivalency can facilitate complex formation when monovalent receptor–ligand interactions are weak. However, enhanced binding of two multivalent binding partners should be avoidable, for example when bivalent receptors ought to utilize multimolecular interactions to cross‐link binding partners. We herein report the first systematic study to assess the criteria deciding whether a bivalent system engages in bivalency‐enhanced interactions or cross‐linking. We used DNA‐instructed self‐assembly to arrange the cucurbit[7]uril–adamantane host–guest system in 70–360 Å distance. Measurements and statistical mechanics analyses revealed that the affinity gain is controlled by 1) the distance between recognition modules, 2) the scaffold flexibility, and, importantly, 3) the strength of the monovalent interaction. We show that the bivalency effect can extend beyond 150 Å and discuss how, on the contrary, weak monovalent interactions reduce the concentration threshold for cross‐linking. The findings are of interest for inhibitor design.     

Peptide‐Decorated Dendrimers and Their Bioapplications

Peptide‐decorated dendrimers (PDDs) are a class of spherical, regular, branched polymers that are modified by peptides covalently attached to their surface. PDDs have been used as protein mimetics, novel biomaterials, and in a wide range of biomedical applications. Since their design and development in the late eighties, poly‐l ‐lysine has been a preferred core structure for PDDs. However, numerous recent innovations in polymer synthesis and ligation chemistry have re‐energized the field and led to the emergence of well‐defined peptide dendrimers with more diverse core structures and functions. This Minireview highlights the development of PDDs driven by significantly improved ligation chemistry incorporating structurally well‐defined peptides and the emerging use of PDDs in imaging and drug development.     

Fabrication of Oligomeric Avidin Scaffolds for Valency‐Controlled Surface Display of Functional Ligands

Multivalent surface display of biomolecules is crucial to study and utilize multivalent biological interactions. However, precise valency control of surface‐displayed ligands remains extremely difficult. Now a series of new oligomeric avidin proteins were fabricated that allow facile control of surface multivalency of biotinylated ligands. Naturally dimeric rhizavidin (RA) was engineered to form a mixture of oligomeric avidin assemblies, and discrete RA oligomers from the dimer to octamer of RA, were homogeneously prepared. These oligomeric avidins are in polygonal forms with expected numbers of stable biotin binding sites. Upon immobilization on low‐density biotin‐coated gold surfaces, RA dimer, trimer, and tetramer scaffolds provided accurate mean residual valencies of 2, 3, and 4, respectively, for biotinylated proteins. Valency‐controlled display of antibody binding protein G on these RA surfaces showed clear valency‐dependent enhancement of antibody capturing stability.     

Non‐Covalent Polyvalent Ligands by Self‐Assembly of Small Glycodendrimers: A Novel Concept for the Inhibition of Polyvalent Carbohydrate–Protein Interactions In Vitro and In Vivo

Polyvalent carbohydrate–protein interactions occur frequently in biology, particularly in recognition events on cellular membranes. Collectively, they can be much stronger than corresponding monovalent interactions, rendering it difficult to control them with individual small molecules. Artificial macromolecules have been used as polyvalent ligands to inhibit polyvalent processes; however, both reproducible synthesis and appropriate characterization of such complex entities is demanding. Herein, we present an alternative concept avoiding conventional macromolecules. Small glycodendrimers which fulfill single molecule entity criteria self‐assemble to form non‐covalent nanoparticles. These particles—not the individual molecules—function as polyvalent ligands, efficiently inhibiting polyvalent processes both in vitro and in vivo. The synthesis and characterization of these glycodendrimers is described in detail. Furthermore, we report on the characterization of the non‐covalent nanoparticles formed and on their biological evaluation.     

A mechanically interlocked bundle

The prototype of an artificial molecular machine consisting of a trisammonium tricationic component interlocked with a tris(crown ether) component to form a molecular bundle with averaged C(3v) symmetry has been designed and synthesized. The system is based on noncovalent interactions, which include 1) N(+)-H...O hydrogen bonds; 2) C-H...O interactions between the CH(2)NH(2) (+)CH(2) protons on three dibenzylammonium-ion-containing arms, which are attached symmetrically to a benzenoid core, and three dibenzo[24]crown-8 macrorings fused onto a triphenylene core; and 3) pi...pi stacking interactions between the aromatic cores. The template-directed synthesis of the mechanically interlocked, triply threaded bundle involves post-assembly covalent modification, that is, the efficient conversion of three azide functions at the ends of the arms of the bound and threaded trication into bulky triazole stoppers, after 1,3-dipolar cycloaddition with di-tert-butylacetylenedicarboxylate to the extremely strong 1:1 adduct that is formed in dichloromethane/acetonitrile (3:2), on account of a cluster effect associated with the paucivalent adduct. Evidence for the averaged C(3v) symmetry of the molecular bundle comes from absorption and luminescence data, as well as from electrochemical experiments, (1)H NMR spectroscopy, and mass spectrometry. The photophysical properties of the mechanically interlocked bundle are very similar to those of the superbundle that precedes the formation of the bundle in the process of supramolecular assistance to covalent synthesis. Although weak non-nucleophilic bases (e.g., nBu(3)N and iPr(2)NEt) fail to deprotonate the bundle, the strong tBuOK does, as indicated by both luminescence and (1)H NMR spectroscopy. While deprotonation undoubtedly loosens up the interlocked structure of the molecular bundle by replacing relatively strong N(+)-H...O hydrogen bonds by much weaker N-H...O ones, the pi...pi stacking interactions ensure that any structural changes are inconsequential, particularly when the temperature of the solution of the neutral molecular bundle in dichloromethane is cooled down to considerably below room temperature.     

Efficient Self‐Assembly of Di‐, Tri‐, Tetra‐, and Hexavalent Hosts with Predefined Geometries for the Investigation of Multivalency

Coordination‐driven self‐assembly of differently shaped di‐ to hexavalent crown‐ether host molecules is described. A series of [21]crown‐7‐ and [24]crown‐8‐substituted bipyridine and terpyridine ligands was synthetized in a “toolbox” approach. Subsequent coordination to 3d transition metal and ruthenium(II) ions provides an easy and fast access to host assemblies with variable valency and pre‐defined orientations of the crown‐ether moieties. Preliminary isothermal calorimetry (ITC) titrations provided promising results, which indicated the host complexes under study to be suitable for the future investigation of multivalent and cooperative binding. The hosts described herein will also be suitable for the construction of various multiply threaded mechanically interlocked molecules.