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

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Abstract
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. Dengue, a re-emergent human disease that places nearly half of the world's population at risk, threatens to further expand in geographical distribution. The lack of an available effective dengue vaccine has encouraged the search for antiviral drugs as an alternative approach. In recent years, drug discovery through high-throughput screening has become a trend in the search for dengue antivirals. In this study, we developed an image-based dengue high-throughput/high-content assay using prevalent viral strains of three dengue serotypes (DENV1, DENV2 and DENV3) isolated from dengue outbreaks in South America and a laboratory-adapted strain of DENV4. We demonstrated the usefulness of our image-based dengue HT/HCA in identifying potential dengue antivirals by screening a small subset of chemical compounds for inhibition of dengue virus infection in a human-derived host cell line (Huh-7.5), and partially characterized their activities against dengue infection in a mosquito host cell line (C6/36), a distantly-related virus (hepatitis C virus), and an unrelated virus that is transmitted by the same mosquito vector (chikungunya virus).

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