Toward the discovery of novel anti-HIV drugs. Second-generation inhibitors of the cellular ATPase DDX3 with improved anti-HIV activity: synthesis, structure-activity relationship analysis, cytotoxicity studies, and target validation

A hit optimization protocol applied to the first nonnucleoside inhibitor of the ATPase activity of human DEAD-box RNA helicase DDX3 led to the design and synthesis of second-generation rhodanine derivatives with better inhibitory activity toward cellular DDX3 and HIV-1 replication. Additional DDX3 inhibitors were identified among triazine compounds. Biological data were rationalized in terms of structure-activity relationships and docking simulations. Antiviral activity and cytotoxicity of selected DDX3 inhibitors are reported and discussed. A thorough analysis confirmed human DDX3 as a valid anti-HIV target. The compounds described herein represent a significant advance in the pursuit of novel drugs that target HIV-1 host cofactors.     

淮南矿区液压支架配液水质研究及使用建议

通过对淮南矿区液压支架配液水质特点的分析研究,结合MT76-2002标准要求对淮南矿区配液水质的正确使用提出了建议,并对高矿化度矿井水的使用提出了解决方案。     

Monitoring the transesterification reaction with laser spectroscopy

The production of biodiesel is rapidly expanding around the world, making it more important to produce this fuel with more energy efficiency. In this paper, we observed a series of transesterification reactions of soy bean oil and methyl alcohol catalyzed by potassium hydroxide. The observations were made using a non-invasive optical technique. This technique is useful to indicate the endpoint of a transesterification reaction or to determine when this reaction is reaching the state of chemical equilibrium. This study made it possible to improve the follow-up of the transesterification reaction, by optimizing the reaction time with a better monitoring system.     

Asymmetric synthesis and conformational analysis by NMR spectroscopy and MD of Aba- and α-MeAba-containing dermorphin analogues

Dermorphin analogues, containing a (S)‐ and (R)‐4‐amino‐1,2,4,5‐tetrahydro‐2‐benzazepin‐3‐one scaffold (Aba) and the α‐methylated analogues as conformationally constrained phenylalanines, were prepared. Asymmetric phase‐transfer catalysis was unable to provide the (S)‐α‐Me‐o‐cyanophenylalanine precursor for (S)‐α‐MeAba in acceptable enantiomeric purity. However, by using a Schöllkopf chiral auxiliary, this intermediate was obtained in 88 % ee. [(S)‐Aba 3‐Gly 4]dermorphin retained μ‐opioid affinity but displayed an increased δ‐affinity. The corresponding R epimer was considerably less potent. In contrast, the [(R)‐α‐MeAba 3‐Gly 4]dermorphin isomer was more potent than its S epimer. Tar‐MD simulations of both non‐methylated [Aba 3‐Gly 4]dermorphin analogues showed a degree of folding at the C‐terminal residues toward the N terminus of the peptide, without however, adopting a stabilized β‐turn conformation. The α‐methylated analogues, on the other hand, exhibited a type I/I′ β‐turn conformation over the α‐MeAba 3 and Gly 4 residues, which was stabilized by a hydrogen bond involving Tyr 5‐H_N and D ‐Ala 2‐CO.     

Autoproteolytic fragments are intermediates in the oligomerization/aggregation of the Parkinson's disease protein alpha-synuclein as revealed by ion mobility mass spectrometry

Gas-phase protein separation by ion mobility: With its ability to separate the Parkinson's disease protein α-synuclein and its autoproteolytic products-despite the small concentrations of the latter-ion-mobility MS has enabled the characterization of intermediate fragments in in vitro oligomerization-aggregation. In particular, a possible key fragment, the highly aggregating C-terminal fragment, αSyn(72-140), has been revealed.     

Urolithin as a converging scaffold linking ellagic acid and coumarin analogues: design of potent protein kinase CK2 inhibitors

Casein kinase 2 (CK2) is a ubiquitous, essential, and highly pleiotropic protein kinase; its abnormally high constitutive activity is suspected to underlie its pathogenic potential in neoplasia and other relevant diseases. Previously, using different in silico screening approaches, two potent and selective CK2 inhibitors were identified by our group: ellagic acid, a naturally occurring tannic acid derivative (K(i)=20 nM) and 3,8-dibromo-7-hydroxy-4-methylchromen-2-one (DBC, K(i)=60 nM). Comparing the crystallographic binding modes of both ellagic acid and DBC, an X-ray structure-driven merging approach was taken to design novel CK2 inhibitors with improved target affinity. A urolithin moiety is proposed as a possible bridging scaffold between the two known CK2 inhibitors, ellagic acid and DBC. Optimization of urolithin A as the bridging moiety led to the identification of 4-bromo-3,8-dihydroxy-benzo[c]chromen-6-one as a novel, potent and selective CK2 inhibitor, which shows a K(i) value of 7 nM against the protein kinase, representing a significant improvement in affinity for the target compared with the two parent fragments.     

Assorted analytical and spectroscopic techniques for the optimization of the defect-related properties in size-controlled ZnO nanowires

In this article, the important role of the intrinsic defects in size-controlled ZnO nanowires (NWs) which play a critical role in the properties of the NWs, was studied with a combined innovative experimental analysis. The NWs prepared by both the aqueous solution method and chemical vapour deposition process were of increasing length and decreasing size-to-volume (S/V) ratio. The combined approach involved different analytical and spectroscopic techniques and from the correlation between the different measurements, the concentration of the oxygen vacancies jointly with the zinc interstitials defects and the zinc vacancy defects was observed to be positively or negatively correlated, respectively, with the magnitude of the photoluminescence intensity and radiative lifetimes. Furthermore, the experimental results also suggest that the oxygen vacancy defects are not only spatially located on the surface of the NW but an increasing fraction of the total oxygen vacancy defects connected with the green emission is also located in an annulus region beneath the surface as the ZnO NWs elongate. On the other hand, as the donor concentration plays a critical function in the properties of the ZnO NWs, an analytical model was derived for the calculation of the donor concentration of the NWs directly from its reverse-biased current-voltage characteristics obtained from the conductive atomic force microscopy measurements.     

Increasing the thermostability of sucrose phosphorylase by a combination of sequence- and structure-based mutagenesis

Sucrose phosphorylase is a promising biocatalyst for the glycosylation of a wide variety of acceptor molecules, but its low thermostability is a serious drawback for industrial applications. In this work, the stability of the enzyme from Bifidobacterium adolescentis has been significantly improved by a combination of smart and rational mutagenesis. The former consists of substituting the most flexible residues with amino acids that occur more frequently at the corresponding positions in related sequences, while the latter is based on a careful inspection of the enzyme's crystal structure to promote electrostatic interactions. In this way, a variant enzyme could be created that contains six mutations and whose half-life at the industrially relevant temperature of 60 °C has more than doubled compared with the wild-type enzyme. An increased stability in the presence of organic co-solvents could also be observed, although these effects were most noticeable at low temperatures.     

Predicting and rationalizing the effect of surface charge distribution and orientation on nano-wire based FET bio-sensors

A single charge screening model of surface charge sensors in liquids (De Vico et al., Nanoscale, 2011, 3, 706-717) is extended to multiple charges to model the effect of the charge distributions of analyte proteins on FET sensor response. With this model we show that counter-intuitive signal changes (e.g. a positive signal change due to a net positive protein binding to a p-type conductor) can occur for certain combinations of charge distributions and Debye lengths. The new method is applied to interpret published experimental data on Streptavidin (Ishikawa et al., ACS Nano, 2009, 3, 3969-3976) and Nucleocapsid protein (Ishikawa et al., ACS Nano, 2009, 3, 1219-1224).     

Influence of operating parameters on plasma polymerization of acrylic acid in a mesh-to-plate dielectric barrier discharge

Plasma polymerization of acrylic acid is an interesting research subject, since the obtained coatings can have significant biomedical applications due to their high surface density of carboxylic acid groups. In this work, plasma-polymerized acrylic acid (PPAA) films are synthesized using a mesh-to-plate dielectric barrier discharge operated at medium pressure (10.0 kPa). Results clearly show that this reactor setup is able to deposit uniform PPAA films in contrast to the commonly used parallel plate reactor. Moreover, carefully planned experiments are conducted to study the influence of discharge power and monomer concentration on the chemical composition and thickness of the PPAA films. Results clearly show that input power strongly influences the properties of the deposited films: with increasing discharge power, monomer fragmentation in the discharge increases leading to a decrease in carboxylic acid functional groups and a lower polymer deposition rate. The effect of monomer concentration is less pronounced: only at very low monomer concentration (0.1 g/h), a decrease in carboxylic acid functional groups can be observed. The chemical composition and thickness of the PPAA films can thus be tailored by adjusting the operational parameters of the discharge.