Identification of novel compounds inhibiting chikungunya virus-induced cell death by high throughput screening of a kinase inhibitor library.

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