Identification of Novel Compounds Inhibiting Chikungunya Virus-Induced Cell Death by High Throughput Screening of a Kinase Inhibitor Library

Chikungunya virus (CHIKV) is a mosquito-borne arthrogenic alphavirus that causes acute febrile illness in humans accompanied by joint pains and in many cases, persistent arthralgia lasting weeks to years. The re-emergence of CHIKV has resulted in numerous outbreaks in the eastern hemisphere, and threatens to expand in the foreseeable future. Unfortunately, no effective treatment is currently available. The present study reports the use of resazurin in a cell-based high-throughput assay, and an image-based high-content assay to identify and characterize inhibitors of CHIKV-infection in vitro. CHIKV is a highly cytopathic virus that rapidly kills infected cells. Thus, cell viability of HuH-7 cells infected with CHIKV in the presence of compounds was determined by measuring metabolic reduction of resazurin to identify inhibitors of CHIKV-associated cell death. A kinase inhibitor library of 4,000 compounds was screened against CHIKV infection of HuH-7 cells using the resazurin reduction assay, and the cell toxicity was also measured in non-infected cells. Seventy-two compounds showing >= 50% inhibition property against CHIKV at 10 mu M were selected as primary hits. Four compounds having a benzofuran core scaffold (CND0335, CND0364, CND0366 and CND0415), one pyrrolopyridine (CND0545) and one thiazol-carboxamide (CND3514) inhibited CHIKV-associated cell death in a dose-dependent manner, with EC50 values between 2.2 mu M and 7.1 mu M. Based on image analysis, these 6 hit compounds did not inhibit CHIKV replication in the host cell. However, CHIKV-infected cells manifested less prominent apoptotic blebs typical of CHIKV cytopathic effect compared with the control infection. Moreover, treatment with these compounds reduced viral titers in the medium of CHIKV-infected cells by up to 100-fold. In conclusion, this cell-based high-throughput screening assay using resazurin, combined with the image-based high content assay approach identified compounds against CHIKV having a novel antiviral activity -inhibition of virus-induced CPE - likely by targeting kinases involved in apoptosis.

Implications of the Adoption of BISAC for Classifying Library Collections

We analysed the written statements of libraries that have adopted the bookstore model for coherence or lack of coherence with common public library guidelines. We used a text-based Foucauldian genealogical discourse analysis to investigate the written statements used by libraries that have adopted BISAC and other aspects of the bookstore model. Libraries adopting bookstore models such as BISAC should consider the potential consequences of adopting a commercial model for a public entity. This paper has practical implications for libraries considering adopting any aspect of the bookstore model, but especially the BISAC system, as it examines the potential benefits and drawbacks of the bookstore model popular in some libraries with respect to the purposes and goals of public libraries. BISAC application in libraries seems to be part of a trend of applying commercial practices, values and terminology in libraries, perhaps not with the purpose of replacing libraries with bookstores, but with the aim for both systems to converge into a new kind of commercial entity and context. The influence of one kind of system over the other does not seem to be totally reciprocal, since the application of library practices, values and standards in bookstores has not had the same effects and resonance as has occurred in the opposite direction.