The ProTide approach has emerged as a powerful tool to improve the intracellular delivery of nucleotide analogs with antiviral and anticancer activity. Here, we characterized the anti-ZIKV (ZIKV, Zika virus) activity of two ProTides of 2′-C-β-methylguanosine. ProTide UMN-1001 is a 2′-C-β-methylguanosine tryptamine phosphoramidate monoester, and ProTide UMN-1002 is a 2-(methylthio)-ethyl-2′-C-β-methylguanosine tryptamine phosphoramidate diester. UMN-1002 undergoes stepwise intracellular activation to the corresponding nucleotide monophosphate followed by P-N bond cleavage by intracellular histidine triad nucleotide binding protein 1 (Hint1). UMN-1001 is activated by Hint1 but is less cell-permeable than UMN-1002. UMN-1001 and UMN-1002 were found to be more potent than 2′-C-β-methylguanosine against ZIKV in human-derived microvascular endothelial and neuroblastoma cells and in reducing ZIKV RNA replication. Studies with a newborn mouse model of ZIKV infection demonstrated that, while treatment with 2′-C-β-methylguanosine and UMN-1001 was lethal, treatment with UMN-1002 was nontoxic and significantly reduced ZIKV infection. Our data suggests that anchimeric activated ProTides of 2′-C-β-methyl nucleosides should be further investigated for their potential as anti-ZIKV therapeutics.
Bibliographical noteFunding Information:
This work was supported by funds from FAPERJ, CAPES, CNPq, and the University of Minnesota Foundation. M.R.M.S. holds a scholarship from CNPq. The authors wish to thank Dr. Amílcar Tanuri (Instituto de Biologia, UFRJ, Brazil) for kindly providing SH-SY5Y cells and Dr. Andrea T. Da Poian (Instituto de Bioquímica Médica, UFRJ, Brazil) for kindly providing the C6/36 cell line. We thank CENABIO (Centro Nacional de Biologia Estrutural e Bioimagem, UFRJ, RJ, Brazil) for confocal microscopy support. We also acknowledge Sidnei Gomes da Costa and Ronaldo Rocha for technical assistance.
Copyright © 2020 American Chemical Society.
- Zika virus
- antiviral treatment
- nucleoside analogs