Polymeric Prodrugs Targeting Polyamine Metabolism Inhibit Zika Virus Replication

Nanda Kishore Routhu, Ying Xie, Matthew Dunworth, Robert A. Casero, David Oupicky, Siddappa Nagadenahalli Byrareddy

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

The Zika virus (ZIKV) is primarily transmitted via an infected mosquito bite, during sexual intercourse, or in utero mother to child transmission. When a fetus is infected, both neurological malformations and deficits in brain development are frequently manifested. As such, there is a need for vaccines or drugs that may be used to cure ZIKV infections. Metabolic pathways play a crucial role in cell differentiation and development. More importantly, polyamines play a key role in replication and translation of several RNA viruses including ZIKV, Dengue virus, and Chikungunya virus. Here, we present polyamine analogues (BENSpm and PG11047) and their corresponding polymer prodrug derivatives for inhibiting ZIKV infection by intersecting with polyamine catabolism pathways. We tested the compounds against ZIKV African (MR766) and Asian (PRVABC59) strains in human kidney epithelial (Vero) and glioblastoma derived (SNB-19) cell lines. Our results demonstrate potent inhibition of ZIKV viral replication in both cell lines tested. This antiviral effect was mediated by upregulation of two polyamine catabolic enzymes, spermine oxidase and spermidine (SMOX)/spermine N1-acetyltransferase (SAT1) as apparent reduction of ZIKV infection following heterologous expression of SMOX and SAT1. Based on these observations, we infer potential use of these polyamine analogues to treat ZIKV infections.

Original languageEnglish (US)
JournalMolecular Pharmaceutics
DOIs
StateAccepted/In press - Jan 27 2018

Fingerprint

Prodrugs
Polyamines
Virus Replication
Chikungunya virus
Cell Line
Dengue Virus
Spermidine
Spermine
Coitus
RNA Viruses
Bites and Stings
Glioblastoma
Metabolic Networks and Pathways
Culicidae
Antiviral Agents
Cell Differentiation
Polymers
Fetus
Up-Regulation
Vaccines

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery

Cite this

Polymeric Prodrugs Targeting Polyamine Metabolism Inhibit Zika Virus Replication. / Routhu, Nanda Kishore; Xie, Ying; Dunworth, Matthew; Casero, Robert A.; Oupicky, David; Byrareddy, Siddappa Nagadenahalli.

In: Molecular Pharmaceutics, 27.01.2018.

Research output: Contribution to journalArticle

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