Abstract
Zika virus is an emerging arthropod-borne flavivirus for which there are no vaccines or specific therapeutics. We screened a library of 2,000 bioactive compounds for their ability to block Zika virus infection in three distinct cell types with two different strains of Zika virus. Using a microscopy-based assay, we validated 38 drugs that inhibited Zika virus infection, including FDA-approved nucleoside analogs. Cells expressing high levels of the attachment factor AXL can be protected from infection with receptor tyrosine kinase inhibitors, while placental-derived cells that lack AXL expression are insensitive to this inhibition. Importantly, we identified nanchangmycin as apotent inhibitor of Zika virus entry across all cell types tested, including physiologically relevant primary cells. Nanchangmycin also was active against other medically relevant viruses, including West Nile, dengue, and chikungunya viruses that use a similar route of entry. This study provides a resource of small molecules to study Zika virus pathogenesis.
Highlights
Zika virus (ZIKV) is a flavivirus transmitted by Aedes mosquitoes including A. aegypti which is globally widespread
We optimized this assay in human osteosarcoma cells (U2OS) since we have performed many screens in this cell type and these cells are permissive to all arthropodborne viruses we have tested (Moy et al, 2014; Panda et al, 2013; Yasunaga et al, 2014) We first tested whether these cells were permissive to ZIKV infection using 3 different strains of ZIKV: the prototype Uganda/African strain MR766 from 1947, the FSS13025 Cambodian/Asian isolate from 2010, and an Americas-derived virus isolated in 2016, MEX 2-81
We found that dengue virus (DENV) (NGC) and chikungunya virus (CHIKV) (181/25) infect these cultures and that infection is blocked by nanchangmycin (Figure S5) These data suggest that nanchangmycin is a potent inhibitor of flavivirus infection in diverse and primary cell types
Summary
Zika virus (ZIKV) is a flavivirus transmitted by Aedes mosquitoes including A. aegypti which is globally widespread. The World Health Organization has declared that the current ZIKV outbreak is a global emergency, due to the rapid spread of the virus and the association of viral infection with microcephaly (Oliveira Melo et al, 2016; Schuler-Faccini et al, 2016; Tetro, 2016). It is not understood why the 2015–2016 ZIKV pandemic has been so explosive, the fact the virus is endemic in immunologically naïve populations likely contributes. Recent data demonstrates sexual transmission and that the testes can harbor infectious virus for long periods (D’Ortenzio et al, 2016; Turmel et al, 2016)
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