High Content Screening of a Kinase-Focused Library Reveals Compounds Broadly-Active against Dengue Viruses

Dengue virus is a mosquito-borne flavivirus that has a large impact in global health. It is considered as one of the medically important arboviruses, and developing a preventive or therapeutic solution remains a top priority in the medical and scientific community. Drug discovery programs for potential dengue antivirals have increased dramatically over the last decade, largely in part to the introduction of high-throughput assays. In this study, we have developed an image-based dengue high-throughput/high-content assay (HT/HCA) using an innovative computer vision approach to screen a kinase-focused library for anti-dengue compounds. Using this dengue HT/HCA, we identified a group of compounds with a 4-(1-aminoethyl)-N-methylthiazol-2-amine as a common core structure that inhibits dengue viral infection in a human liver-derived cell line (Huh-7.5 cells). Compounds CND1201, CND1203 and CND1243 exhibited strong antiviral activities against all four dengue serotypes. Plaque reduction and time-of-addition assays suggests that these compounds interfere with the late stage of viral infection cycle. These findings demonstrate that our image-based dengue HT/HCA is a reliable tool that can be used to screen various chemical libraries for potential dengue antiviral candidates. © 2013 Cruz et al.

Keywords

alpha2a interferon, chloroquine, phosphotransferase inhibitor, ribavirin, affinity chromatography, animal cell, antiviral activity, Chikungunya alphavirus, computer model, computer program, controlled study, Dengue virus, dose response, drug structure, genotype, high throughput screening, human, human cell, nonhuman, nucleotide sequence, peptide library, validation process, viral disease immunofluorescence assay, Antiviral Agents, Cell Line, Dengue Virus, Drug Discovery, Hepatocytes, High-Throughput Screening Assays, Humans, Microbial Sensitivity Tests