Artificial aldolases from peptide dendrimer combinatorial libraries

Peptide dendrimers were investigated as synthetic models for aldolase enzymes. Combinatorial libraries were prepared with aldolase active residues such as lysine and proline placed at the dendrimer core or near the surface. On-bead selection for aldolase activity was carried out using the dye-labelled 1,3-diketone 1a, suitable for covalent trapping of enamine-reactive side-chains, and the fluorogenic enolization probe 6. Aldolase dendrimers catalyzed the aldol reaction of acetone, dihydroxyacetone and cyclohexanone with nitrobenzaldehyde. Much like enzymes, the dendrimers exhibited strong aldolase activity in aqueous medium, but were also active in organic solvent. Dendrimer-catalyzed aldol reactions reached complete conversion in 3 h at 25 degrees C with 1 mol% catalyst and gave aldol products with up to 65% ee. A positive dendritic effect in catalysis was observed with both lysine and proline based aldolase dendrimer catalysts.     

Textural Characterization of Silica and Silica-Alumina Gels: Comparison of Different Techniques

The porous texture of silica and silica-alumina hydrogels has been studied by means of thermoporometry measurements. The texture of the xerogels resulting from spray-drying of silica-alumina hydrogels is then evaluated by different methods: BET, Hg-porosimetry and thermoporometry. As each method is based on different physical principles and assumptions, differences are observed between the results. However, these results are complementary and their comparison leads to a better knowledge of the texture of the catalyst particles. A good agreement is observed between thermoporometry and nitrogen adsorption-desorption measurements, whereas mercury porosimetry results are very different. Silica-alumina gels appear as mainly mesoporous materials.     

Combining Topology and Sequence Design for the Discovery of Potent Antimicrobial Peptide Dendrimers against Multidrug‐Resistant Pseudomonas aeruginosa

Multidrug‐resistant opportunistic bacteria, such as Pseudomonas aeruginosa, represent a major public health threat. Antimicrobial peptides (AMPs) and related peptidomimetic systems offer an attractive opportunity to control these pathogens. AMP dendrimers (AMPDs) with high activity against multidrug‐resistant clinical isolates of P. aeruginosa and Acinetobacter baumannii were now identified by a systematic survey of the peptide sequences within the branches of a distinct type of third‐generation peptide dendrimers. Combined topology and peptide sequence design as illustrated here represents a new and general strategy to discover new antimicrobial agents to fight multidrug‐resistant bacterial pathogens.     

Peptide dendrimer enzyme models for ester hydrolysis and aldolization prepared by convergent thioether ligation

Peptide dendrimers with multiple histidines or N-terminal prolines efficiently catalyze ester hydrolysis or aldol reactions in aqueous medium. Part of the catalytic proficiency of these dendritic enzyme models stems from multivalency effects observed in G2, G3 and G4 dendrimers displaying multiple catalytic groups in their branches. To study multivalency in higher generation systems, G4, G5 and G6 peptide dendrimers were prepared by a convergent assembly. Thus, peptide dendrimers bearing four or eight chloroacetyl groups at their N-termini underwent multiple thioether ligation with G2 and G3 peptide dendrimers with a cysteine residue at their focal point, to give G4, G5 and G6 dendrimers containing up to 341 amino acids, including multiple histidines or N-terminal prolines. While the efficiency of the esterase catalysts was comparable to that of their lower generation analogs, a remarkable reactivity increase was observed in G5 and G6 aldolase dendrimers.     

Discovery of α7-nicotinic receptor ligands by virtual screening of the chemical universe database GDB-13

The chemical universe database GDB-13 enumerates 977 million organic molecules up to 13 atoms of C, N, O, Cl, and S that are virtually possible following simple rules for chemical stability and synthetic feasibility. Analogs of nicotine were identified in GDB-13 using the city-block distance in MQN-space (CBD(MQN)) as a similarity measure, combined with a restriction eliminating problematic structural elements. The search was carried out with a Web browser available at www.gdb.unibe.ch . This virtual screening procedure selected 31?504 analogs of nicotine from GDB-13, from which 48 were known nicotinic ligands reported in Chembl. An additional 60 virtual screening hits were purchased and tested for modulation of the acetylcholine signal at the human α7 nAChR expressed in Xenopus oocytes, which led to the identification of three previously unknown inhibitors. These experiments demonstrate for the first time the use of GDB-13 for ligand discovery.     

A mathematical model of aging-related and cortisol induced hippocampal dysfunction

Background  

The hippocampus is essential for declarative memory synthesis and is a core pathological substrate for Alzheimer's disease (AD), the most common aging-related dementing disease. Acute increases in plasma cortisol are associated with transient hippocampal inhibition and retrograde amnesia, while chronic cortisol elevation is associated with hippocampal atrophy. Thus, cortisol levels could be monitored and managed in older people, to decrease their risk of AD type hippocampal dysfunction. We generated an in silicomodel of the chronic effects of elevated plasma cortisol on hippocampal activity and atrophy, using the systems biology mark-up language (SBML). We further challenged the model with biologically based interventions to ascertain if cortisol associated hippocampal dysfunction could be abrogated.     

Definition and measurement of the normalized electrical impedance of lossy piezoelectric resonators for ultrasonic transducers

Relevant equivalent circuit parameters and values of material constants of a piezoelectric resonator can be determined from measurements of its electrical input impedance as a function of frequency. The complex electrical impedance curves and the associated critical frequencies are the basis of this characterization by the piezoelectric resonance method. In this paper, the previously introduced concept of normalized electrical impedance of the lossy resonator, extended to include piezoelectric losses, is applied to the analysis of the effects of different types of intrinsic losses on peak values, bandwidths and characteristic frequencies. The resulting impedance patterns depend solely on the electromechanical coupling coefficient and the loss tangents, providing a useful tool for the analysis of low-Q resonators. The normalized impedance is experimentally evaluated from the basic data provided by an HP 4194A impedance analyser by means of specifically developed ASP programs.     

STM vizualization of thiol-containing peptide dendrimers on Au(111)

Peptide dendrimers assembled by solid-phase peptide synthesis using a branching diamino acid at every 2(nd) or 3(rd) position provide readily accessible synthetic model systems for proteins and enzymes. They adopt a globular shape by topology rather than by folding. Peptide dendrimers of 2(nd) and 3(rd) generation functionalized with a cysteine or cystine residue in the core were adsorbed on Au(111) surface and imaged by STM at air, under UHV, or in solution. The dendrimers appear as globular features with dimensions suggesting an extended flattened conformation, forming both single globules and ordered arrays on the surface. These images represent the first direct visualization of peptide dendrimer enzyme models.