High content screening of a kinase-focused library reveals compounds broadly-active against dengue viruses

PLoS Negl Trop Dis. 2013;7(2):e2073. doi: 10.1371/journal.pntd.0002073. Epub 2013 Feb 21.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antiviral Agents / chemistry
  • Antiviral Agents / isolation & purification*
  • Antiviral Agents / pharmacology*
  • Cell Line
  • Dengue Virus / drug effects*
  • Drug Discovery / methods*
  • Hepatocytes / virology
  • High-Throughput Screening Assays*
  • Humans
  • Microbial Sensitivity Tests

Substances

  • Antiviral Agents

Grants and funding

A.C. Koishi and C.N. Duarte dos Santos are supported by fellowships from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq). This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MEST) (No. 2012-00011), Gyeonggi-do and KISTI. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.