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The flavivirus genome encodes a single polyprotein precursor requiring multiple cleavages by host and viral proteases in order to produce the individual proteins that constitute an infectious virion. Previous studies have revealed that the NS2B cofactor of the viral NS2B-NS3 heterocomplex protease displays a conformational dynamic between active and inactive states. Here, we developed a conformational switch assay based on split luciferase complementation (SLC) to monitor the conformational change of NS2B and to characterize candidate allosteric inhibitors. Binding of an active-site inhibitor to the protease resulted in a conformational change of NS2B and led to significant SLC enhancement. Mutagenesis of key residues at an allosteric site abolished this induced conformational change and SLC enhancement. We also performed a virtual screen of NCI library compounds to identify allosteric inhibitors, followed by in vitro biochemical screening of the resultant candidates. Only three of these compounds, NSC135618, 260594, and 146771, significantly inhibited the protease of Dengue virus 2 (DENV2) in vitro, with IC50 values of 1.8 μM, 11.4 μM, and 4.8 μM, respectively. Among the three compounds, only NSC135618 significantly suppressed the SLC enhancement triggered by binding of active-site inhibitor in a dose-dependent manner, indicating that it inhibits the conformational change of NS2B. Results from virus titer reduction assays revealed that NSC135618 is a broad spectrum flavivirus protease inhibitor, and can significantly reduce titers of DENV2, Zika virus (ZIKV), West Nile virus (WNV), and Yellow fever virus (YFV) on A549 cells in vivo, with EC50 values in low micromolar range. In contrast, the cytotoxicity of NSC135618 is only moderate with CC50 of 48.8 μM on A549 cells. Moreover, NSC135618 inhibited ZIKV in human placental and neural progenitor cells relevant to ZIKV pathogenesis. Results from binding, kinetics, Western blot, mass spectrometry and mutagenesis experiments unambiguously demonstrated an allosteric mechanism for inhibition of the viral protease by NSC135618. [ABSTRACT FROM AUTHOR]

The article focuses on a survey by the periodical in which leading scientist from academia and industry presents notable papers related to microbiome research. It presents top five papers from scientist including "Demonstrated in rodents that an obese phenotype could be transferred or reversed by fecal transplant of the microbiota" by Peter DiStefano of California.

The article offers information on the premier microbial meeting by the ISME Journal and Nature Reviews Microbiology to be held in Cairns, Australia from August 17-22, 2008.

The article reports on the results of Min Li and colleagues' study of a multidisciplinary approach to link the functions of microbial gut bacteria, the human microbiome, to host metabolic phenotypes. A description of the experimental set-up and measurement methods is presented. The study pinpointed specific microorganisms that have defined roles in human metabolism using a functional genomics approach.

The article presents several charts and tables that shows trends in microbiome research including top ten institutions receiving microbiome funding, patenting related to the microbiome, and notable trial and studies.

The article reports that the replacement of the transcription signals of the rabies virus phosphoprotein gene with internal ribosome entry sites from poliovirus enables the downregulation of phosphoprotein expression and can render rabies virus avirulent. Positive-strand RNA viruses have a restricted host range. The translational control of individual genes is a promising strategy to attenuate replication and virulence and might provide a basis for a new vaccine.

The article discusses the result of a study published in "Cellular Microbiology." The study which investigated the three-dimensional structure of the mycelia of the fungal pathogen Aspergillus fumigatus found out that hyphae are held together by a hydrophobic glue. The glue could provide protection against drug action and immune defenses.

The article focuses on symbiosis and the research conducted by Marquez and others. The researchers found a tripartite association between a virus, a fungus and a plant that provided thermal tolerance to the plant and the fungus. Two other Tripartite symbiosis encompassing viruses, between insects, bacteria and bacteriophage have been reported so far. Details of the research procedure along with clarifications is provided.

The article focuses on biofilms and the research conducted by Paul Rainey, Soren Molin and colleagues. The researchers revealed how bacterial species interact and evolve to form a stable biofilm. Pseudomonas putida and Acinetobacter were taken and experimented to find the metabolic partnership and biofilm development. Spatial structure is innately linked to the evolution of new functions in biofilm communities as per the study.

The article presents an overview of the topics covered in the October 2005 issue of the journal. Topics include the significant threat of Picornaviridae to human and animal health, host-pathogen interactions, food microbiology and food quality, TRIM proteins, and bacteriocins, the small antibacterial peptides produced by lactic acid bacteria.

The article focuses on a paper published in "Nature" reveals a new aspect of plastid biology which shows two plastid proteins which have a role in symbioses with fungi and bacteria. Scientists have studied symbiotic interactions of bacteria and fungi with the leguminous plant Lotus japonicus. The receivers uncovered structural features of CASTOR and POLLUX genes that match an archaeal multimeric calcium-gated potassium channel.

The article focuses on two papers published in "Nature" which report that microbial diversity is area-dependent and that the taxa-area relationship is a universal law. Two groups of scientists investigated whether the size of the area sampled has any relationship with microbial diversity using culture-independent sampling methods to document species diversity. Microbiologists have realized that microbial communities are structured communities that obey the universal taxa-area relationship.

The article discusses various topics published within the issue, including one by Andrew Travers and Georgi Muskhelishvili on RNA promoters and DNA supercoiling and another by Ildefonso Cases and Victor de Lorenzo on bacterial mechanisms.

The article focuses on the research regarding cytokinesis monitoring during bacterial development conducted by J. Y. Matroule. The study had linked initiation of development in bacterium Caulobacter crescentus with the completion of cytokinesis. It found that cytokinesis started cell development in Caulobacter and that communication between the cells were closely monitored.

The article discusses the result of the study on the variable domains of bacterial chromosome of Escherichia coli (E. coli), which shows to be much smaller than what was previously thought. As the domain size affects DNA repair, transcription and replication, chromosome in small domains are more easily repaired. The author noted that this new development is helpful in understanding the organization of E. coli chromosome which is relevant in developing solutions to E. coli infections.

The article discusses the new mechanism of ecological coexistence by a microbial community of the sympatric bacteria Achromatium species in sediments, as accounted in the periodical "Environmental Microbiology." It is indicated that such species live together due to its differences in carbon metabolism or redox chemistry.

The article cites a study that reveals the complexity of the entrainment of the model fungus Neurospora crassa clock. Rather than a simple transcriptional feedback regulatory loop, translation and protein stability also impinge on clock control. Light, the most important environmental training signal, can switch clock genes on, and promote degradation of clock proteins.

The article cites a study that uses a global transcriptome approach in studying the comparability of the pathogenic strategies of viruses in different cell types. Pseudorabies virus (PRV) and herpes simplex virus type 1 (HSV-1) are alpha-herpesviruses that have conserved genome organization, virion structure and replication cycles. It is observed that there are changes in oxidative-stress gene transcription late in both PRV and HSV-1 infection.