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.
Highlights
Dengue virus (DENV) is an important mosquito-borne pathogen responsible for causing dengue fever (DF) and the more severe, life-threatening dengue hemorrhagic fever/shock syndrome (DHF/DSS) [1]
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 high-throughput/high-content assay (HT/high-content assay (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, and an unrelated virus that is transmitted by the same mosquito vector
Summary
Dengue virus (DENV) is an important mosquito-borne pathogen responsible for causing dengue fever (DF) and the more severe, life-threatening dengue hemorrhagic fever/shock syndrome (DHF/DSS) [1]. The presence of more than 1 dengue serotype in a geographical area contribute to the persistence of epidemics, as immunity acquired against one dengue serotype does not confer long-term protective immunity against heterologous serotypes [8]. Individuals that have acquired humoral immunity against one dengue serotype may be pre-disposed to DHF/DSS when subsequently infected with a heterologous serotype through antibody-dependent enhancement [9,10]. Present estimates by the World Health Organization place nearly 2.5 billion people at risk of dengue, with approximately 50 million cases of dengue infection and 20 thousand mortalities occurring annually [11]
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