Identification of a small-molecule inhibitor of dengue virus using a replicon system

• Published in: Archives of virology Vol. 157; no. 4; pp. 681 - 688
• Main Authors: Hsu, Yu-Chen, Chen, Nai-Chi, Chen, Po-Chiang, Wang, Chun-Chung, Cheng, Wei-Chieh, Wu, Huey-Nan
• Format: Journal Article
• Language: English
• Published: Vienna Springer Vienna 01.04.2012; Springer; Springer Nature B.V
• Subjects: Animals; Antiviral Agents; Antiviral Agents - chemistry; Antiviral Agents - isolation & purification; Antiviral Agents - pharmacology; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Cell Line; chemistry; Dengue fever; Dengue virus; Dengue Virus - drug effects; drug effects; Drug Evaluation, Preclinical; Drug Evaluation, Preclinical - methods; Fundamental and applied biological sciences. Psychology; Genes, Reporter; genetics; Humans; Infectious Diseases; isolation & purification; luciferase; Luciferases; Luciferases - genetics; Luciferases - metabolism; Medical Microbiology; metabolism; methods; Microbiology; Miscellaneous; Molecular biology; Molecular Structure; Original Article; Pathogens; pharmacology; Plasmids; Proteins; public health; replicon; Replicon - drug effects; RNA; screening; Staining and Labeling; subtropics; translation (genetics); Vaccines; Virology; Virus Internalization; Virus Internalization - drug effects; Virus Replication; Virus Replication - drug effects; Viruses; Taiwan; Japanese Encephalitis Virus; Dengue Hemorrhagic Fever; DENV Infection; Dengue Shock Syndrome; Dengue Virus; Virus; Identification; Flaviviridae; Dengue virus; Flavivirus; Dengue group virus
• ISSN: 0304-8608; 1432-8798; 1432-8798
• DOI: 10.1007/s00705-012-1224-z

Dengue virus (DENV) is a mosquito-borne human pathogen that causes a serious public-health threat in tropical and subtropical regions of the world. Neither a vaccine to prevent nor an effective therapeutic agent to treat DENV infection is currently available. We established a stable cell line harboring a luciferase-reporting DENV subgenomic replicon to screen for inhibitors of DENV. A total of 14,400 small-molecule (MW < 500 Da) chemicals were evaluated for their ability to reduce luciferase reporter activity in cell lysates. One effective compound was identified from the screening. This compound was found to reduce virus production but did not block virus entry in virus-based assay. Mode-of-action analysis revealed that this inhibitor suppressed viral RNA replication but did not affect replicon translation. This compound potentially could be developed as an anti-DENV agent and might be useful for dissecting the molecular mechanism of DENV replication.