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Hepatitis C virus (HCV) is a human pathogen with high morbidity. The HCV NS3/4A protease is essential for viral replication and is one of the top three drug targets. Several drugs targeting the protease have been developed, but drug-resistant mutant strains emerged. Here, we screened a library and synthesized a novel class of small molecules based on a tryptophan derivative scaffold identified as HCV NS3/4A protease inhibitors that are active against both wild type and mutant form of the protease. Only the compounds with predicted binding poses not affected by the most frequent mutations in the active site were selected for experimental validation. The antiviral activities were evaluated by replicon and enzymatic assays. Twenty-two compounds were found to inhibit HCV with EC50 values ranging between 0.64 and 63 μM with compound 22 being the most active. In protease assays, 22 had a comparable inhibition profile for the common mutant HCV GT1b D168A and the wild-type enzyme. However, in the same assay, the potency of the approved drug, simeprevir, decreased 5.7-fold for the mutant enzyme relative to the wild type. The top three inhibitors were also tested against four human serine proteases and were shown to be specific to the viral protease. The fluorescence-based cell viability assay demonstrated a sufficient therapeutic range for the top three candidates.

G-protein coupled receptors (GPCRs) are implicated in many diseases and attractive targets for drug discovery. Peptide fragments derived from protein ligands of GPCRs are commonly used as probes of GPCR function and as leads for drug development. However, these peptide fragments lack the structural integrity of their parent full-length protein ligands and often show low receptor affinity, which limits their research and therapeutic values. It remains a challenge to efficiently generate high affinity peptide inhibitors of GPCRs. We have investigated a combinational approach involving the synthetic covalent linkage of two low affinity peptide fragments to determine if the strategy can yield high affinity GPCR inhibitors. We examined this design approach using the chemokine receptor CXCR4 as a model of GPCR system. Here, we provide a proof of concept demonstration by designing and synthesizing two peptides, AR5 and AR6, that combine a peptide fragment derived from two viral ligands of CXCR4, vMIP-II and HIV-1 envelope glycoprotein gp120. AR5 and AR6 display nanomolar binding affinity, in contrast to the weak micromolar CXCR4 binding of each peptide fragment alone, and inhibit HIV-1 entry via CXCR4. Further studies were carried out for the representative peptide AR6 using western blotting and site-directed mutagenesis in conjunction with molecular dynamic simulation and binding free energy calculation to determine how the peptide interacts with CXCR4 and inhibits its downstream signaling. These results demonstrate that this combinational approach is effective for generating nanomolar active inhibitors of CXCR4 and may be applicable to other GPCRs.

The combination of fluoropolymer and nano‐thermite has been a research focus in the field of materials in the field of energy and storage in recent years, but it faces the problem of uneven mixing of fluoropolymer and nano‐aluminum powder (nAl). Therefore, it is of great significance to obtain a fluorine/aluminum uniform composite by a solid/solid phase mixing method. In this paper, Pickering emulsions effectively blend difficult‐to‐mix powders of nAl and solid bulk fluoroelastomers on the micro‐ and nanoscale. The emulsion was prepared by Pickering emulsion with an ethyl acetate solution of fluororubber as the oil phase and perfluorocarboxylic acid‐modified nano‐aluminum powder as a surfactant. The effects of oil/water ratio, fluororubber/aluminum ratio, and standing time on the stability of the emulsion were studied. The nano‐aluminum powder/fluororubber composite microspheres were prepared and their morphology, thermal decomposition, and combustion properties were characterized. The results showed that the emulsion prepared with the oil/water ratio of 1:8 and m(fluororubber):m(modified nano‐aluminum powder) of 5:1 had good stability and dispersion. The transmission electron microscopy (TEM) and scanning electron microscopy (SEM) results showed that the complex was observed to be regular spherical and the size was about 10 µm, and the composite microspheres prepared by the Pickering emulsion had good. The TG‐DSC results showed that the decomposition of the composite microspheres started at about 450 °C and finished at 519 °C. The composite microspheres prepared in this paper are stable and rapid in exotherm, with a combustion rate of 33 cm s−1 and excellent combustion performance. The Pickering emulsion introduces a new idea for the preparation of thermite by mixing the solid reactants at the micro‐nano level without introducing substances that reduce the energy of the system. [ABSTRACT FROM AUTHOR]

In order to further regulate equivalent circulating density (ECD), a novel downhole apparatus for reducing circulating pressure in high-temperature and high-pressure wells, the suction-type ECD reduction tool, was devised. The utilisation of this tool enables the bottomhole pressure of the equivalent circulating density to be attained in close proximity to its hydrostatic pressure, thereby facilitating the attainment of deeper drilling depths. The tool is composed primarily of a screw motor, scroll blades, annular seals, universal joints, and drilling columns. The tool operates by utilising the suction effect and hydraulic energy extracted from the circulating fluid by the screw motor, which is then converted into mechanical energy to create suction and enhance the flow energy of the drilling fluid within the annulus at the bottom of the well, thereby reducing the equivalent circulating density. Furthermore, based on ANSYS-FLUENT analysis simulations, the alteration of pressure drop characteristics in response to varying drilling fluid densities, displacements, and tool sizes was modelled. The simulation results demonstrate that the pressure drop effect is 1.0 MPa when the drilling fluid density is 1.2 g/cm3, 1.7 MPa when the drilling fluid density is 1.5 g/cm3, and 1.9 MPa when the drilling fluid density is 1.8 g/cm3. A pressure drop of approximately 2.3 MPa was observed when the drilling fluid density was 2.0 g/cm3. The maximum pressure drop is achievable with a flow rate ranging from 1500 to 2500 L/min. A maximum pressure drop of 2.3 MPa is observed when the flow rate is within the range of 1500 to 2500 L/min. Two distinct viscosity values (0.02 and 0.06 kg/(m·s)) were employed to assess the impact of viscosity on pressure drop characteristics in a suction-type ECD tool. The results demonstrated that the pressure drop remained largely unaltered, indicating that viscosity had minimal influence on this parameter. The flow rate emerged as the primary factor affecting pressure drop, with viscosity exerting a relatively minor effect. [ABSTRACT FROM AUTHOR]