In Vitro and in Vivo Characterization of the Anti-Zika Virus Activity of ProTides of 2′-C-β-Methylguanosine

Marcos Romário Matos De Souza, Marcela Sabino Cunha, Aniekan Okon, Fábio Luís Lima Monteiro, Loraine Campanati, Carston R. Wagner, Luciana Jesus Da Costa

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1650-1658
Number of pages9
JournalACS Infectious Diseases
Volume6
Issue number7
DOIs
StatePublished - Jul 10 2020

Bibliographical note

Funding 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.

Keywords

  • ProTides
  • Zika virus
  • antiviral treatment
  • nucleoside analogs
  • prodrugs

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