Zika antiviral chemotherapy: identification of drugs and promising starting points for drug discovery from an FDA-approved library

Abstract

Background The recent epidemics of Zika virus (ZIKV) implicated it as the cause of serious and potentially lethal congenital conditions such microcephaly and other central nervous system defects, as well as the development of the Guillain-Barré syndrome in otherwise healthy patients. Recent findings showed that anti-Dengue antibodies are capable of amplifying ZIKV infection by a mechanism similar to antibody-dependent enhancement, increasing the severity of the disease. This scenario becomes potentially catastrophic when the global burden of Dengue and the advent of the newly approved anti-Dengue vaccines in the near future are taken into account. Thus, antiviral chemotherapy should be pursued as a priority strategy to control the spread of the virus and prevent the complications associated with Zika. Methods Here we describe a fast and reliable cell-based, high-content screening assay for discovery of anti-ZIKV compounds. This methodology has been used to screen the National Institute of Health Clinical Collection compound library, a small collection of FDA-approved drugs. Results and conclusion From 725 FDA-approved compounds triaged, 29 (4%) were found to have anti-Zika virus activity, of which 22 had confirmed (76% of confirmation) by dose-response curves. Five candidates presented selective activity against ZIKV infection and replication in a human cell line. These hits have abroad spectrum of chemotypes and therapeutic uses, offering valuable opportunities for selection of leads for antiviral drug discovery.

Azithromycin Inhibits the Replication of Zika Virus

“…Using large screening strategies, several compounds have been found to have an in vitro activity against ZIKV including anticancer, immunosuppressant, antiviral, antiparasitic, antibiotics, antirheumatic, statin, iron chelator, antihemetic, antidepressant, and antifungal drugs [3,[6][7][8][9][10]. However, most of these drugs cannot be used during pregnancy, their safety during pregnancy has not been demonstrated, and/or the effective concentration is higher than the maximum plasma concentration [6] In vitro efficacy of several antibiotics against arboviruses has been reported [6] but to our knowledge, data on the efficacy of antibiotics to limit the growth of ZIKV are limited to preliminary results with daptomycin (lipopeptid), azithromycin (AZ) (macrolide) and kitasamycin (macrolide) [6][7][8]11,12].…”

The Race To Find Antivirals for Zika Virus

“…On the contrary, the pyrimidine synthesis inhibitors tested (NITD008, CID 91632869, finasteride, brequinar, and 6-azauridine) were able to reduce viral multiplication to different levels, with EC 50 s ranging from submicromolar (brequinar) to 3.2 M (6-azauridine). Remarkably, 6-azauridine, an anticancer drug and viral inhibitor, was also identified (EC 50 , 2.3 M; SI, Ͼ33.3) in another screening (24). Regarding NITD008, this compound also exhibited antiviral activity in A129 mice deficient in type I interferon receptor treated with 50 mg/kg/day of the drug, as all vehicle-treated mice died within 12 days after ZIKV infection, whereas 50% of the NITD008-treated animals survived without developing any neurological signs (25).…”

“…By means of a cell-based high-content screening assay, different FDA-approved molecules included in the National Institutes of Health (NIH) clinical collection compound library were reported to present moderate activity against ZIKV infection in Huh-7 cells (24). Among these were palonosetron (EC 50 , 16.3 M; SI, Ͼ3.1), an antiemetic, kitasamycin (EC 50 , 41.7 M; SI, Ͼ12), a broad-spectrum antimicrobial, and lovastatin (EC 50 , 20.7 M; SI, Ͼ2.5), a hypolipidemic agent that inhibits cholesterol biosynthesis.…”

Zika Virus: What Have We Learnt Since the Start of the Recent Epidemic?

“…Likewise, the pyrimidine synthesis inhibitors NITD008, CID 91632869, finasteride, brequinar, 6-azauridine, gemcitabine, and 5-fluorouracil reduced viral multiplication to different levels (Pascoalino et al, 2016;Adcock et al, 2017;Kuivanen et al, 2017). Even more, NITD008 improved survival rates in treated mice infected with ZIKV .…”