title: High content screening of a kinase-focused library reveals compounds broadly-active against dengue viruses.
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.
authors: Center for Neglected Diseases Drug Discovery (CND3), Institut Pasteur Korea, Seongnam-si, Gyeonggi-do, South Korea.
authors: Deu John M
authors: DJ
authors: Cruz
authors: Andrea Cristine
authors: AC
authors: Koishi
authors: Juliana Bosso
authors: JB
authors: Taniguchi
authors: Xiaolan
authors: X
authors: Li
authors: Rafaela
authors: R
authors: Milan Bonotto
authors: Joo Hwan
authors: JH
authors: No
authors: Keum Hyun
authors: KH
authors: Kim
authors: Sungmin
authors: S
authors: Baek
authors: Hee Young
authors: HY
authors: Kim
authors: Marc Peter
authors: MP
authors: Windisch
authors: Ana Luiza
authors: AL
authors: Pamplona Mosimann
authors: Luana
authors: L
authors: de Borba
authors: Michel
authors: M
authors: Liuzzi
authors: Michael Adsetts Edberg
authors: MA
authors: Hansen
authors: Claudia Nunes
authors: CN
authors: Duarte dos Santos
authors: Lucio Holanda
authors: LH
authors: Freitas-Junior
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D002460:Cell Line; D003716:Dengue Virus / Q000187:drug effects*; D055808:Drug Discovery / Q000379:methods*; D022781:Hepatocytes / Q000821:virology; D057166:High-Throughput Screening Assays; D006801:Humans; D008826:Microbial Sensitivity Tests
chemical_list: D000998:Antiviral Agents