Discovery of an imidazonaphthyridine and a riminophenazine as potent anti-Zika virus agents through a replicon-based high-throughput screening

Author(s)

Fernandes, Rafaela Sachetto ^[1] ; de Godoy, Andre Schutzer ^[1] ; Santos, Igor Andrade ^[2] ; Noske, Gabriela Dias ^[1] ; de Oliveira, Ketllyn Irene Zagato ^[1] ; Gawriljuk, Victor Oliveira ^[1] ; Jardim, Ana Carolina Gomes ^[2] ; Oliva, Glaucius ^[1]

Affiliation

^[1] Univ Sao Paulo, Phys Inst Sao Carlos, Ave Joao Dagnone 1100, BR-13563120 Sao Carlos - Brazil

^[2] Univ Fed Uberlandia, Inst Biomed Sci, Ave Amazonas 1700, Bloco 4C Sala 216, BR-38405317 Uberlandia, MG - Brazil

• Document type: Journal article
• Source: VIRUS RESEARCH; v. 299, JUL 2 2021.
• Web of Science Citations: 0

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-Barre ` 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. (AU)

• FAPESP's process: 18/05130-3 - Construction and characterization of a ZIKV sub-genomic replicon system for the discovery of antiviral agents.
• Grantee: Rafaela Sachetto Fernandes
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 16/19712-9 - Structural characterization of Zika virus proteins and search for antiviral agents
• Grantee: Andre Schutzer de Godoy
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 13/07600-3 - CIBFar - Center for Innovation in Biodiversity and Drug Discovery
• Grantee: Glaucius Oliva
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC