A phenotypic assay to identify chikungunya virus inhibitors targeting the nonstructural protein nsP2
Autor(es): Lucas-Hourani Marianne, Lupan Alex-ru, Desprès Philippe, Thoret Sylviane, Pamlard Olivier, Dubois Joëlle, Guillou Catherine, Tangy Frédéric, Vidalain Pierre-Olivier, Munier-Lehmann Hélène
Resumo: Chikungunya virus (CHIKV) is a mosquito-transmitted pathogen responsible for an acute infection of abrupt onset, characterized by high fever, polyarthralgia, myalgia, headaches, chills, - rash. In 2006, CHIKV was responsible for an epidemic outbreak of unprecedented magnitude in the Indian Ocean, stressing the need for therapeutic approaches. Since then, we have acquired a better underst-ing of CHIKV biology, but we are still missing active molecules against this reemerging pathogen. We recently reported that the nonstructural nsP2 protein of CHIKV induces a transcriptional shutoff that allows the virus to block cellular antiviral response. This was demonstrated using various luciferase-based reporter gene assays, including a trans-reporter system where Gal4 DNA binding domain is fused to Fos transcription factor. Here, we turned this assay into a high-throughput screening system to identify small molecules targeting nsP2-mediated shutoff. Among 3040 molecules tested, we identified one natural compound that partially blocks nsP2 activity - inhibits CHIKV replication in vitro. This proof of concept suggests that similar functional assays could be developed to target other viral proteins mediating a cellular shutoff - identify innovative therapeutic molecules.
Imprenta: Journal of Biomolecular Screening, v. 18, n. 2, p. 172-179, 2013
Identificador do objeto digital: 10.1177/1087057112460091
Descritores: Chikungunya virus - Cell ; Chikungunya virus - DNA ; Chikungunya virus - Proteins ; Chikungunya Virus - Virus ; Chikungunya virus - Chikungunya fever ; Chikungunya virus - Epidemic ; Chikungunya virus - Public health
Data de publicação: 2013
