The Hepatitis B Virus Ribonuclease H Is Sensitive to Inhibitors of the Human Immunodeficiency Virus Ribonuclease H and Integrase Enzymes

Nucleos(t)ide analog therapy blocks DNA synthesis by the hepatitis B virus (HBV) reverse transcriptase and can control the infection, but treatment is life-long and has high costs and unpredictable long-term side effects. The profound suppression of HBV by the nucleos(t)ide analogs and their ability to cure some patients indicates that they can push HBV to the brink of extinction. Consequently, more patients could be cured by suppressing HBV replication further using a new drug in combination with the nucleos(t)ide analogs. The HBV ribonuclease H (RNAseH) is a logical drug target because it is the second of only two viral enzymes that are essential for viral replication, but it has not been exploited, primarily because it is very difficult to produce active enzyme. To address this difficulty, we expressed HBV genotype D and H RNAseHs in E. coli and enriched the enzymes by nickel-affinity chromatography. HBV RNAseH activity in the enriched lysates was characterized in preparation for drug screening. Twenty-one candidate HBV RNAseH inhibitors were identified using chemical structure-activity analyses based on inhibitors of the HIV RNAseH and integrase. Twelve anti-RNAseH and anti-integrase compounds inhibited the HBV RNAseH at 10 μM, the best compounds had low micromolar IC50 values against the RNAseH, and one compound inhibited HBV replication in tissue culture at 10 μM. Recombinant HBV genotype D RNAseH was more sensitive to inhibition than genotype H. This study demonstrates that recombinant HBV RNAseH suitable for low-throughput antiviral drug screening has been produced. The high percentage of compounds developed against the HIV RNAseH and integrase that were active against the HBV RNAseH indicates that the extensive drug design efforts against these HIV enzymes can guide anti-HBV RNAseH drug discovery. Finally, differential inhibition of HBV genotype D and H RNAseHs indicates that viral genetic variability will be a factor during drug development. © 2013 Tavis et al

Speed : Visions of an Accelerated Age

A major publication as part of an international project organised by The Photographers Gallery and Whitechapel Art Gallery in London, the Netherlands Design Institute in Amsterdam, and the Macdonald Stewart Art Centre in Guelph. Contains texts (many in reprint) by more than twenty authors – including renowned writers such as Virilio, Ballard, Wollen and Illich – who address the theme of speed from diverse perspectives: social, cultural, scientific, literary, philosophical, art historical, environmental, etc. Numerous issues are considered in relation to the desire for speed in modern technological culture. Topics discussed include: landscape, transportation and communications technologies, mobility and links between cinema and the Autobahn (highway) within the context of Nazi Germany. Includes photographs of selected works from exhibitions at The Photographers Gallery, the Whitechapel Art Gallery and the Macdonald Stewart Art Centre; thematic images selected by the editors with texts by J.G. Ballard; list of works; brief biographical notes. Circa 250 bibl. ref

Sociologists of the Unexpected: Edward A. Ross and Georg Simmel on the Unintended Consequences of Modernity

Groß M. Sociologists of the Unexpected: Edward A. Ross and Georg Simmel on the Unintended Consequences of Modernity. The American Sociologist. 2003;34(4):40-58