Purification and characterization of bioactive compounds extracted from Suaeda maritima leaf and its impact on pathogenicity of Pseudomonas aeruginosa in Catla catla fingerlings.

Incidence of various dreadful microbial infections and the development of antibiotic resistance by infection causative microbes are the main reasons for reducing aquaculture productivity. Hence, there is an immense need for the discovery of alternative and efficient treatment for quick recovery of diseased fishes. In the present study, Suaeda maritima leaf extracts (hexane, diethyl ether, ethanol, and water) were screened for in vitro and in vivo antibacterial and antioxidant activities.

Nanostructured Nickel/Silica Catalysts for Continuous Flow Conversion of Levulinic Acid to γ-Valerolactone.

Selective transformation of levulinic acid (LA) to γ-valerolactone (GVL) using novel heterogeneous catalysts is one of the promising strategies for viable biomass processing. In this framework, we developed a continuous flow process for the selective hydrogenation of LA to GVL using several nanostructured Ni/SiO catalysts. The structural, textural, acidic, and redox properties of Ni/SiO catalysts, tuned by selectively varying the Ni amount from 5 to 40 wt %, were critically investigated using numerous materials characterization techniques.

Discovery of Novel Allosteric HCV NS5B Inhibitors. 2. Lactam-Containing Thiophene Carboxylates.

Lomibuvir () is a non-nucleoside, allosteric inhibitor of the hepatitis C virus NS5B polymerase with demonstrated clinical efficacy. Further development efforts within this class of inhibitor focused on improving the antiviral activity and physicochemical and pharmacokinetic properties. Recently, we reported the development of this series, leading to compound , a molecule with comparable potency and an improved physicochemical profile relative to .

Integrated Experimental and Theoretical Study of Shape-Controlled Catalytic Oxidative Coupling of Aromatic Amines over CuO Nanostructures.

We have synthesized CuO nanostructures with flake, dandelion-microsphere, and short-ribbon shapes using solution-phase methods and have evaluated their structure-performance relationship in the heterogeneous catalysis of liquid-phase oxidative coupling reactions. The formation of nanostructures and the morphological evolution were confirmed by transmission electron microscopy, scanning electron microscopy, X-ray diffraction analysis, X-ray photoelectron spectroscopy, Raman spectroscopy, energy-dispersive X-ray spectroscopy, elemental mapping analysis, and Fourier transform infrared spectroscopy. CuO nanostructures with different morphologies were tested for the catalytic oxidative coupling of aromatic amines to imines under solvent-free conditions.

Discovery of Novel Thiophene-Based, Thumb Pocket 2 Allosteric Inhibitors of the Hepatitis C NS5B Polymerase with Improved Potency and Physicochemical Profiles.

The hepatitis C viral proteins NS3/4A protease, NS5B polymerase, and NS5A are clinically validated targets for direct-acting antiviral therapies. The NS5B polymerase may be inhibited directly through the action of nucleosides or nucleotide analogues or allosterically at a number of well-defined sites. Herein we describe the further development of a series of thiophene carboxylate allosteric inhibitors of NS5B polymerase that act at the thumb pocket 2 site.

Benzimidazole-containing HCV NS5A inhibitors: effect of 4-substituted pyrrolidines in balancing genotype 1a and 1b potency.

The treatment of HCV with highly efficacious, well-tolerated, interferon-free regimens is a compelling clinical goal. Trials employing combinations of direct-acting antivirals that include NS5A inhibitors have shown significant promise in meeting this challenge. Herein, we describe our efforts to identify inhibitors of NS5A and report on the discovery of benzimidazole-containing analogs with subnanomolar potency against genotype 1a and 1b replicons.

Nonstructural protein 5A (NS5A) and human replication protein A increase the processivity of hepatitis C virus NS5B polymerase activity in vitro.

Unlabelled: The precise role(s) and topological organization of different factors in the hepatitis C virus (HCV) RNA replication complex are not well understood. In order to elucidate the role of viral and host proteins in HCV replication, we have developed a novel in vitro replication system that utilizes a rolling-circle RNA template. Under close-to-physiological salt conditions, HCV NS5BΔ21, an RNA-dependent RNA polymerase, has poor affinity for the RNA template.

Genotypic and phenotypic analyses of hepatitis C virus variants observed in clinical studies of VX-222, a nonnucleoside NS5B polymerase inhibitor.

VX-222, a thiophene-2-carboxylic acid derivative, is a selective nonnucleoside inhibitor of the hepatitis C virus (HCV) NS5B RNA-dependent RNA polymerase. In phase 1 and 2 clinical studies, VX-222 demonstrated effective antiviral efficacy, with substantial reductions in plasma HCV RNA in patients chronically infected with genotype 1 HCV. To characterize the potential for selection of VX-222-resistant variants in HCV-infected patients, the HCV NS5B gene was sequenced at baseline and during and after 3 days of VX-222 dosing (monotherapy) in a phase 1 study.

In vitro phenotypic characterization of hepatitis C virus NS3 protease variants observed in clinical studies of telaprevir.

Telaprevir is a linear, peptidomimetic small molecule that inhibits hepatitis C virus (HCV) replication by specifically inhibiting the NS3·4A protease. In phase 3 clinical studies, telaprevir in combination with peginterferon and ribavirin (PR) significantly improved sustained virologic response (SVR) rates in genotype 1 chronic HCV-infected patients compared with PR alone. In patients who do not achieve SVR after treatment with telaprevir-based regimens, variants with mutations in the NS3·4A protease region have been observed.

Characterization of V36C, a novel amino acid substitution conferring hepatitis C virus (HCV) resistance to telaprevir, a potent peptidomimetic inhibitor of HCV protease.

We characterized a novel substitution conferring moderate resistance to telaprevir, a peptidomimetic inhibitor of hepatitis C virus protease. V36C conferred a 4.0-fold increase in the telaprevir 50% inhibitory concentration in an enzyme assay and a 9.

Molecular characterization of Jatropha genetic resources through inter-simple sequence repeat (ISSR) markers.

The genetic diversity among eight Jatropha species and three Jatropha curcas accessions were analyzed using ISSR-PCR. Nine ISSR primers generated reproducible amplification banding pattern of 61 polymorphic bands out of 64 scored accounting for 98.14% polymorphism across the species.

Education of persons with intellectual disabilities in India.

Historically in India, persons with disabilities enjoyed co-existence, though at different times, the treatment and attitudes were at variance. Out of all the types of disabilities, an intellectual disability poses greater challenges than the other types. The families of persons with intellectual disabilities do also have needs different from others, which cannot be segregated from the needs of children with intellectual disability.

FURSMASA: a new approach to rapid scoring functions that uses a MD-averaged potential energy grid and a solvent-accessible surface area term with parameters GA fit to experimental data.

We demonstrate a new approach to the development of scoring functions through the formulation and parameterization of a new function, which can be used both for rapidly ranking the binding of ligands to proteins and for estimating relative aqueous molecular solubilities. The intent of this work is to introduce a new paradigm for creation of scoring functions, wherein we impose the following criteria upon the function: (1) simple; (2) intuitive; (3) requires no postparameterization tweaking; (4) can be applied (without reparameterization) to multiple target systems; and (5) can be rapidly evaluated for any potential ligand. Following these criteria, a new function, FURSMASA (function for rapid scoring using an MD-averaged grid and the accessible surface area) has been developed.

Novel thiol-based TACE inhibitors. Part 2: Rational design, synthesis, and SAR of thiol-containing aryl sulfones.

A series of potent thiol-containing aryl sulfone TACE inhibitors were designed and synthesized. The SAR and MMP selectivity of the series were investigated. In particular, compound 8b showed excellent in vitro potency against the isolated enzyme and good selectivity over MMP-2, -7, -8, -9, and -13.

Phenotypic characterization of resistant Val36 variants of hepatitis C virus NS3-4A serine protease.

In patients chronically infected with hepatitis C virus (HCV) strains of genotype 1, rapid and dramatic antiviral activity has been observed with telaprevir (VX-950), a highly selective and potent inhibitor of the HCV NS3-4A serine protease. HCV variants with substitutions in the NS3 protease domain were observed in some patients during telaprevir dosing. In this study, purified protease domain proteins and reconstituted HCV subgenomic replicons were used for phenotypic characterization of many of these substitutions.

Phenotypic and structural analyses of hepatitis C virus NS3 protease Arg155 variants: sensitivity to telaprevir (VX-950) and interferon alpha.

Telaprevir (VX-950) is a highly selective, potent inhibitor of the hepatitis C virus (HCV) NS3.4A serine protease. It has demonstrated strong antiviral activity in patients chronically infected with genotype 1 HCV when dosed alone or in combination with peginterferon alfa-2a.

Inhibitors of hepatitis C virus NS3.4A protease. Effect of P4 capping groups on inhibitory potency and pharmacokinetics.

Reversible tetrapeptide-based compounds have been shown to effectively inhibit the hepatitis C virus NS3.4A protease. Inhibition of viral replicon RNA production in Huh-7 cells has also been demonstrated.

Novel thiol-based TACE inhibitors: rational design, synthesis, and SAR of thiol-containing aryl sulfonamides.

A series of potent thiol-containing aryl sulfonamide TACE inhibitors was designed and synthesized. The SAR and MMP selectivity of the series were investigated. In particular, compound 4b has shown excellent in vitro potency against the isolated TACE enzyme and good selectivity over MMP-2, -7, -8, -9, and -13.

High Quality Performance of High-throughput GeneChip® Probe Array System.

A high-throughput GeneChip® probe array platform was established. This system offers automated processing of 96 samples in the industry standard 96-well plate format. We demonstrate that this new technology can deliver the same performance as the standard cartridge probe arrays.

Preclinical profile of VX-950, a potent, selective, and orally bioavailable inhibitor of hepatitis C virus NS3-4A serine protease.

VX-950 is a potent, selective, peptidomimetic inhibitor of the hepatitis C virus (HCV) NS3-4A serine protease, and it demonstrated excellent antiviral activity both in genotype 1b HCV replicon cells (50% inhibitory concentration [IC50] = 354 nM) and in human fetal hepatocytes infected with genotype 1a HCV-positive patient sera (IC50 = 280 nM). VX-950 forms a covalent but reversible complex with the genotype 1a HCV NS3-4A protease in a slow-on, slow-off process with a steady-state inhibition constant (K(i)*) of 7 nM. Dissociation of the covalent enzyme-inhibitor complex of VX-950 and genotype 1a HCV protease has a half-life of almost an hour.

Viral and cellular RNA helicases as antiviral targets.

Although there has been considerable progress in the development of antiviral agents in recent years, there is still a pressing need for new drugs both to improve on the properties of existing agents and to combat the problem of viral resistance. Helicases, both viral and human, have recently emerged as novel targets for the treatment of viral infections. Here, we discuss the role of these enzymes, factors affecting their potential as drug targets and progress in the development of agents that inhibit their activity using the hepatitis C virus-encoded helicase NS3 and the cellular helicase DDX3 adopted for use by HIV-1 as examples.

In vitro studies of cross-resistance mutations against two hepatitis C virus serine protease inhibitors, VX-950 and BILN 2061.

VX-950 is a potent, small molecule, peptidomimetic inhibitor of the hepatitis C virus (HCV) NS3.4A serine protease and has recently been shown to possess antiviral activity in a phase I trial in patients chronically infected with genotype 1 HCV. In a previous study, we described in vitro resistance mutations against either VX-950 or another HCV NS3.

Recent developments in the design of specific Matrix Metalloproteinase inhibitors aided by structural and computational studies.

It has been 10 years since a 3-dimensional structure of the catalytic domain of a Matrix Metalloprotease (MMP) was revealed for the first time in 1994. More than 80 structures of different MMPs in apo and inhibited forms, determined by X-ray crystallography and NMR methods, have been published by the end of year 2003. A large number of very potent inhibitors have been disclosed in published and patent literature.

Organizational aspects of special schools for mental retardation in India.

The aim of this study was to find out areas for improvement in the system of special schools for mental retardation in India and to provide policy guidance. It attempted to find out regional variations between special schools in terms of service facilities, numbers of students enrolled in both day-care and residential facilities and composition and profile of human resources vis-à-vis students and special schools and to compare them with trends for the whole of India. The results indicate that enrollment of girl students is very low (37%) and that the staff-to-student ratio on average is 1:6 leaving scope for better utilization of the existing infrastructure.

BREED: Generating novel inhibitors through hybridization of known ligands. Application to CDK2, p38, and HIV protease.

In this work we describe BREED, a method for the generation of novel inhibitors from structures of known ligands bound to a common target. The method is essentially an automation of the common medicinal chemistry practice of joining fragments of two known ligands to generate a new inhibitor. The ligand-bound target structures are overlaid, all overlapping bonds in all pairs of ligands are found, and the fragments on each side of each matching bond are swapped to generate the new molecules.