Kinetic Properties of Carbohydrate–Lectin Interactions: FimH Antagonists

The lectin FimH is terminally expressed on type 1 pili of uropathogenic Escherichia coli (UPEC), which is the main cause of urinary tract infections (UTIs). FimH enables bacterial adhesion to urothelial cells, the initial step of infection. Various mannose derivatives have been shown to antagonize FimH and are therefore considered to be promising therapeutic agents for the treatment of UTIs. As part of the preclinical development process, when the kinetic properties of FimH antagonists were examined by surface plasmon resonance, extremely low dissociation rates (k_off) were found, which is uncommon for carbohydrate–lectin interactions. As a consequence, the corresponding half‐lives (t_1/2) of the FimH antagonist complexes are above 3.6 h. For a therapeutic application, extended t_1/2 values are a prerequisite for success, since the target occupancy time directly influences the in vivo drug efficacy. The long t_1/2 value of the tested FimH antagonists further confirms their drug‐like properties and their high therapeutic potential.     

Carbohydrate–PNA and Aptamer–PNA Conjugates for the Spatial Screening of Lectins and Lectin Assemblies

Nucleic acid architectures offer intriguing opportunities for the interrogation of structural properties of protein receptors. In this study, we performed a DNA‐programmed spatial screening to characterize two functionally distinct receptor systems: 1) structurally well‐defined Ricinus communis agglutinin (RCA₁₂₀), and 2) rather ill‐defined assemblies of L‐selectin on nanoparticles and leukocytes. A robust synthesis route that allowed the attachment both of carbohydrate ligands—such as N‐acetyllactosamine (LacNAc), sialyl‐Lewis‐X (sLe^X), and mannose—and of a DNA aptamer to PNAs was developed. A systematically assembled series of different PNA–DNA complexes served as multivalent scaffolds to control the spatial alignments of appended lectin ligands. The spatial screening of the binding sites of RCA₁₂₀ was in agreement with the crystal structure analysis. The study revealed that two appropriately presented LacNAc ligands suffice to provide unprecedented RCA₁₂₀ affinity (K_D=4 μM ). In addition, a potential secondary binding site was identified. Less dramatic binding enhancements were obtained when the more flexible L‐selectin assemblies were probed. This study involved the bivalent display both of the weak‐affinity sLe^X ligand and of a high‐affinity DNA aptamer. Bivalent presentation led to rather modest (sixfold or less) enhancements of binding when the self‐assemblies were targeted against L‐selectin on gold nanoparticles. Spatial screening of L‐selectin on the surfaces of leukocytes showed higher affinity enhancements (25‐fold). This and the distance–activity relationships indicated that leukocytes permit dense clustering of L‐selectin.     

Structure and Stability of Carbohydrate–Lipid Interactions. Methylmannose Polysaccharide–Fatty Acid Complexes

We report a detailed study of the structure and stability of carbohydrate–lipid interactions. Complexes of a methylmannose polysaccharide (MMP) derivative and fatty acids (FAs) served as model systems. The dependence of solution affinities and gas‐phase dissociation activation energies (E_a) on FA length indicates a dominant role of carbohydrate–lipid interactions in stabilizing (MMP+FA) complexes. Solution ¹H NMR results reveal weak interactions between MMP methyl groups and FA acyl chain; MD simulations suggest the complexes are disordered. The contribution of FA methylene groups to the E_a is similar to that of heats of transfer of n‐alkanes from the gas phase to polar solvents, thus suggesting that MMP binds lipids through dipole‐induced dipole interactions. The MD results point to hydrophobic interactions and H‐bonds with the FA carboxyl group. Comparison of collision cross sections of deprotonated (MMP+FA) ions with MD structures suggests that the gaseous complexes are disordered.     

Microarray Analysis of Oligosaccharide‐Mediated Multivalent Carbohydrate–Protein Interactions and Their Heterogeneity

Carbohydrate–protein interactions (CPIs) are involved in a wide range of biological phenomena. Hence, the characterization and presentation of carbohydrate epitopes that closely mimic the natural environment is one of the long‐term goals of glycosciences. Inspired by the multivalency, heterogeneity and nature of carbohydrate ligand‐mediated interactions, we constructed a combinatorial library of mannose and galactose homo‐ and hetero‐glycodendrons to study CPIs. Microarray analysis of these glycodendrons with a wide range of biologically important plant and animal lectins revealed that oligosaccharide structures and heterogeneity interact with each other to alter binding preferences.     

Assessing Carbohydrate–Carbohydrate Interactions by NMR Spectroscopy: The Trisaccharide Epitope from the Marine Sponge Microciona prolifera

Weak recognition processes : Weak calcium‐mediated carbohydrate–carbohydrate interactions have been detected by DOSY and TRNOESY NMR methods by employing a gold glyconanoparticle as a multivalent system. In addition, 3D models of trisaccharide‐Ca^II‐trisaccharide complexes based on results from molecular dynamics simulations are proposed.

     

Monosaccharide Derivatives with Low‐Nanomolar Lectin Affinity and High Selectivity Based on Combined Fluorine–Amide,Phenyl–Arginine,Sulfur–π, and Halogen Bond Interactions

The design of small and high‐affinity lectin inhibitors remains a major challenge because the natural ligand binding sites of lectin are often shallow and have polar character. Herein we report that derivatizing galactose with un‐natural structural elements that form multiple non‐natural lectin–ligand interactions (orthogonal multipolar fluorine–amide, phenyl–arginine, sulfur–π, and halogen bond) can provide inhibitors with extraordinary affinity (low nanomolar) for the model lectin, galectin‐3, which is more than five orders of magnitude higher than the parent galactose; moreover, is selective over other galectins.     

Crystallinity Degree of Polyethylene Tubular Blown Films Evaluated by X-ray Diffraction and Density Methods: An Evaluation of the Interfacial Contribution

An experimental study is reported of the relationship between the degree of crystallinity of polyethylene tubular blown films obtained from x-ray diffraction and from density. The comparison shows that there are significant differences between the two techniques, and the values for percentage of crystallinity as determined by the density method are higher than those determined by the x-ray diffraction method. The main reason for these differences is the inclusion of the interfacial contribution to the measured density. The possible application of the analysis of the equation obtained for density crystallinity versus x-ray crystallinity in the evaluation of amorphous and crystalline domains in the interfacial region is discussed.     

Clay–polymer nanocomposite coatings for imaging application

Aqueous coatings of intercalated smectite clay particles in a polymeric matrix have been evaluated for application in inkjet media. The state of clay intercalation, as measured by X-ray diffraction (XRD) technique, plays a significant role in determining the crystallinity of the polymer and the transparency and gloss of the coatings. Results of practical tests on the nanocomposite coatings operating as inkjet-receiving layers are discussed.     

Structural Chemistry: The Last 50 Years as Seen by an X-ray Crystallographer

Some aspects of the evolution of structural chemistry are described from the personal perspective of a student of Jack Dunitz who started working for a Ph.D. in crystal chemistry in the mid-1960s. The importance and the change of emphasis of X-ray crystal structure determination through the decades is sketched and related to technological advances. Activities beyond standard structure determination by single-crystal and powder diffraction, some of them significantly underdeveloped, are indicated. While crystal structure determination has become an important, if not indispensable, analytical tool supporting the widespread objectives of the synthetic chemists, structural chemistry has also developed a deep physical understanding of the concept of structure at the atomic length scale and enabled the organization of an enormous volume of individual observations based on the notions of chemical bonding.     

An improved prediction result of entropic‐FV model for vapor–liquid equilibria of solvent–polymer systems

In this work, entropic expressions of UNIFAC‐FV and Entropic‐FV models were evaluated by using an extensive database of infinite dilution vapor–liquid equilibrium (VLE) data of athermal systems containing polypropylene, polyethylene, and polyisobutylene. For the infinite dilution athermal systems, performance of the Entropic‐FV model was better than that of the UNIFAC‐FV model. Then, finite concentration VLE data of non‐athermal systems that consisted of 16 polymers and 36 solvents containing a large variety of solvent–polymer systems ranging from nonpolar to polar substances were considered to optimized 46 pairs of group interaction parameters of the Entropic‐FV model. For systems containing polar solvents of three types of solvents studied, revised group interaction parameters gave significant improvements from 17.9 to 13.0% average absolute deviation (AAD) of solvent activities. For overall results, improvements were achieved from 15.1 to 12.4% AAD. © 2005 Wiley Periodicals, Inc. J Appl Polym Sci 97: 1145–1153, 2005     

C–(N)–S–H and N–A–S–H gels: Compositions and solubility data at 25°C and 50°C

Calcium silicate hydrates containing sodium [C–(N)–S–H], and sodium aluminosilicate hydrates [N–A–S–H] are the dominant reaction products that are formed following reaction between a solid aluminosilicate precursor (eg, slags, fly ash, metakaolin) and an alkaline activation agent (eg NaOH) in the presence of water. To gain insights into the thermochemical properties of such compounds, C–(N)–S–H and N–A–S–H gels were synthesized with compositions: 0.8≤Ca/Si≤1.2 for the former, and 0.25≤Al/Si≤0.50 (atomic units) for the latter. The gels were characterized using thermogravimetric analysis (TGA), scanning electron microscopy with energy‐dispersive X‐ray microanalysis (SEM‐EDS), and X‐ray diffraction (XRD). The solubility products (K_S0) of the gels were established at 25°C and 50°C. Self‐consistent solubility data of this nature are key inputs required for calculation of mass and volume balances in alkali‐activated binders (AABs), and to determine the impacts of the precursor chemistry on the hydrated phase distributions; in which, C–(N)–S–H and N–A–S–H compounds dominate the hydrated phase assemblages.     

X‐ray Structures and Feasibility Assessment of CLK2 Inhibitors for Phelan–McDermid Syndrome

CLK2 inhibition has been proposed as a potential mechanism to improve autism and neuronal functions in Phelan–McDermid syndrome (PMDS). Herein, the discovery of a very potent indazole CLK inhibitor series and the CLK2 X‐ray structure of the most potent analogue are reported. This new indazole series was identified through a biochemical CLK2 Caliper assay screen with 30k compounds selected by an in silico approach. Novel high‐resolution X‐ray structures of all CLKs, including the first CLK4 X‐ray structure, bound to known CLK2 inhibitor tool compounds (e.g., TG003, CX‐4945), are also shown and yield insight into inhibitor selectivity in the CLK family. The efficacy of the new CLK2 inhibitors from the indazole series was demonstrated in the mouse brain slice assay, and potential safety concerns were investigated. Genotoxicity findings in the human lymphocyte micronucleus test (MNT) assay are shown by using two structurally different CLK inhibitors to reveal a major concern for pan‐CLK inhibition in PMDS.     

In situ X-ray analysis under controlled potential conditions: An innovative setup and its application to the investigation of ultrathin films electrodeposited on Ag(1 1 1)

An innovative setup to combine electrochemical and in situ surface X-ray diffraction (SXRD) measurements is described. This electrochemical cell has a different design from the other ones commonly used for X-ray diffraction studies. It allows the sample surface to stay always completely immersed into the solution under controlled potential conditions even during the SXRD measurements. The X-ray beam crosses the liquid (about 1 cm) and the cell walls. Because of the high X-ray energy, the beam attenuation is negligible and by an appropriate positioning of the detector arm slits it is possible to minimize the diffuse scattering induced by the liquid and cell walls in order to still detect the minima of the crystal truncation rods (CTRs). The liquid solution in the cell is managed by a special device, which allows the controlled exchange of the electrolyte solutions necessary in the electrochemical atomic layer epitaxy (ECALE) growth. The whole setup can be remotely controlled from outside the experimental hutch by a dedicated computer. As an example we report measurements on S layers deposited at underpotential on the Ag(1 1 1) surface, and on CdS films of increasing thickness.     

Exploring the Structural Space of the Galectin‐1–Ligand Interaction

Galectin‐1 is a tumor‐associated protein recognizing the Galβ1‐4GlcNAc motif of cell‐surface glycoconjugates. Herein, we report the stepwise expansion of a multifunctional natural scaffold based on N‐acetyllactosamine (LacNAc). We obtained a LacNAc mimetic equipped with an alkynyl function on the 3′‐hydroxy group of the disaccharide facing towards a binding pocket adjacent to the carbohydrate‐recognition domain. It served as an anchor motif for further expansion by the Sharpless–Huisgen–Meldal reaction, which resulted in ligands with a binding mode almost identical to that of the natural carbohydrate template. X‐ray crystallography provided a structural understanding of the galectin‐1–ligand interactions. The results of this study enable the development of bespoke ligands for members of the galectin target family.     

Promotion effect in Pt–ZnO catalysts for selective hydrogenation of crotonaldehyde to crotyl alcohol: A structural investigation

Pt–ZnO catalysts prepared from different precursors, H₂PtCl₆ and Pt(NH₃)₄(NO₃)₂, and reduced at increased temperatures are used to achieve high selectivity towards crotyl alcohol in hydrogenation of crotonaldehyde. The ex-chloride catalyst shows a higher activity and selectivity than the ex-nitrate one. Transmission electron microscopy, electron diffraction, high-resolution imaging, energy dispersive X-ray spectroscopy and element mapping are used to characterize the catalysts in order to correlate the microstructure to the catalytic behavior. PtZn alloy formation is confirmed for both ex-chloride and ex-nitrate catalysts reduced at 673 K. The metal particles in ex-nitrate catalyst are smaller in size than those in ex-chloride. In most aggregates of the ex-chloride catalyst, chlorine is distributed homogeneously with low concentration (<1%). The higher chlorine concentration in some region leads to local morphology and microstructure changes. Influences of the observed structural features such as alloy formation, particle size difference, formation of ill-defined material, and chlorine distribution are discussed.     

An experimental approach to delineate the reaction mechanism of Ti3AlC2 MAX-Phase formation

A comprehensive reaction mechanism of Ti₃AlC₂ MAX-phase formation from its elemental powders while spark plasma sintering has been proposed. Microstructural evaluation revealed that Al-rich TiAl₃ intermetallic forms at around 660 °C once Al melts. Gradual transition from TiAl₃ to Ti-rich TiAl and Ti₃Al intermetallic phases occurs between 700 °C and 1200 °C through formation of layered structure due to diffusion of Al from periphery toward the centre of Ti particles. Formation of TiC and Ti₃AlC transient carbide phases were observed to occur through two different reactions beyond 1000 °C. Initially, TiC forms due to interaction of Ti and C, which further reacts with TiAl and Ti and gives rise to Ti₃AlC. Later, Ti₃AlC also forms due to diffusion of C into Ti₃Al above 1200 °C. Above 1300 °C, Ti₃AlC phase decomposes into Ti₂AlC MAX-phase and TiC in presence of unreacted C. Finally, Ti₂AlC and TiC reacts together to from Ti₃AlC₂ MAX-phase above 1350 °C and completes at 1500 °C.