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Discovery of an imidazonaphthyridine and a riminophenazine as potent anti-Zika virus agents through a replicon-based high-throughput screening.
FERNANDES, Rafaela Sachetto; GODOY, Andre Schutzer; SANTOS, Igor Andrade; NOSKE, Gabriela Dias; OLIVEIRA, Ketllyn Irene Zagato; GAWRILJUK, Victor Oliveira; JARDIM, Ana Carolina Gomes; OLIVA, Glaucius.
Abstract: The 2015/16 Zika virus (ZIKV) epidemic led to almost 1 million confirmed cases in 84 countries and was associated to the development of congenital microcephaly and Guillain-Barr´e syndrome. More recently, a ZIKV African lineage was identified in Brazil raising concerns about a future outbreak. The long-term consequences of viral infection emphasizes the need for the development of effective anti-ZIKV drugs. In this study, we developed and characterized a ZIKV replicon cell line for the screening of viral replication inhibitors. The replicon system was developed by engineering the IRES-Neo cassette into the 3? UTR terminus of the ZIKV Rluc DNA construct. After in vitro transcription, replicon RNA was used to transfect BHK-21 cells, that were selected with G418, thus generating the BHK-21-RepZIKV_IRES-Neo cell line. Through this replicon-based cell system, we identified two molecules with potent anti-ZIKV activities, an imidazonaphthyridine and a riminophenazine, both from the MMV/DNDi Pandemic Response Box library of 400 drug-like compounds. The imidazonaphthyridine, known as RO8191, showed remarkable selectivity against ZIKV, while the riminophenazine, the antibiotic Clofazimine, could act as a non-nucleoside analog inhibitor of viral RNA-dependent RNA polymerase (RdRp), as evidenced both in vitro and in silico. The data showed herein supports the use of replicon-based assays in high-throughput screening format as a biosafe and reliable tool for antiviral drug discovery.
Virus Research
v. 299, p. 198388-1-198388-9 - Ano: 2021
Fator de Impacto: 2,934
    @article={003029961,author = {FERNANDES, Rafaela Sachetto; GODOY, Andre Schutzer; SANTOS, Igor Andrade; NOSKE, Gabriela Dias; OLIVEIRA, Ketllyn Irene Zagato; GAWRILJUK, Victor Oliveira; JARDIM, Ana Carolina Gomes; OLIVA, Glaucius.},title={Discovery of an imidazonaphthyridine and a riminophenazine as potent anti-Zika virus agents through a replicon-based high-throughput screening},journal={Virus Research},note={v. 299, p. 198388-1-198388-9},year={2021}}