TY - JOUR
T1 - Obatoclax, saliphenylhalamide and gemcitabine inhibit Zika virus infection in vitro and differentially affect cellular signaling, transcription and metabolism
AU - Kuivanen, Suvi
AU - Bespalov, Maxim M.
AU - Nandania, Jatin
AU - Ianevski, Aleksandr
AU - Velagapudi, Vidya
AU - De Brabander, Jef K.
AU - Kainov, Denis E.
AU - Vapalahti, Olli
N1 - Funding Information:
We thank Ms. Irina Suomalainen for help with IFA experiments. This study was supported by Jane and Aatos Erkko Foundation (to D.E.K.), three-year research grant from University of Helsinki (No. 465/51/2014, to D.E.K.), Juselius Foundation, Academy of Finland and Helsinki University Hospital Funds (to O.V.), and the Robert A. Welch Foundation (I-1422, to J.K.D.B.).
Publisher Copyright:
© 2016 Elsevier B.V.
PY - 2017/3/1
Y1 - 2017/3/1
N2 - An epidemic of Zika virus (ZIKV) infection associated with congenital abnormalities such as microcephaly, is ongoing in the Americas and the Pacific. Currently there are no approved therapies to treat this emerging viral disease. Here, we tested three cell-directed broad-spectrum antiviral compounds against ZIKV replication using human retinal pigment epithelial (RPE) cells and a low-passage ZIKV strain isolated from fetal brain. We found that obatoclax, SaliPhe, and gemcitabine inhibited ZIKV infections at noncytotoxic concentrations. Moreover, all three compounds prevented production of viral RNA and proteins as well as activation of cellular caspase 8, 3 and 7. However, these compounds differentially affected ZIKV-mediated transcription, translation and posttranslational modifications of cellular factors as well as metabolic pathways indicating that these agents possess different mechanisms of action. Interestingly, combination of obatoclax and SaliPhe at nanomolar concentrations had a synergistic effect against ZIKV infection. Thus, our results provided the foundation for development of broad-spectrum cell-directed antivirals or their combinations for treatment of ZIKV and other emerging viral diseases.
AB - An epidemic of Zika virus (ZIKV) infection associated with congenital abnormalities such as microcephaly, is ongoing in the Americas and the Pacific. Currently there are no approved therapies to treat this emerging viral disease. Here, we tested three cell-directed broad-spectrum antiviral compounds against ZIKV replication using human retinal pigment epithelial (RPE) cells and a low-passage ZIKV strain isolated from fetal brain. We found that obatoclax, SaliPhe, and gemcitabine inhibited ZIKV infections at noncytotoxic concentrations. Moreover, all three compounds prevented production of viral RNA and proteins as well as activation of cellular caspase 8, 3 and 7. However, these compounds differentially affected ZIKV-mediated transcription, translation and posttranslational modifications of cellular factors as well as metabolic pathways indicating that these agents possess different mechanisms of action. Interestingly, combination of obatoclax and SaliPhe at nanomolar concentrations had a synergistic effect against ZIKV infection. Thus, our results provided the foundation for development of broad-spectrum cell-directed antivirals or their combinations for treatment of ZIKV and other emerging viral diseases.
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U2 - 10.1016/j.antiviral.2016.12.022
DO - 10.1016/j.antiviral.2016.12.022
M3 - Article
C2 - 28049006
AN - SCOPUS:85008312120
SN - 0166-3542
VL - 139
SP - 117
EP - 128
JO - Antiviral Research
JF - Antiviral Research
ER -