Human DDX3 protein is a valuable target to develop broad spectrum antiviral agents

Annalaura Brai, Roberta Fazi, Cristina Tintori, Claudio Zamperini, Francesca Bugli, Maurizio Sanguinetti, Egidio Stigliano, José Esté, Roger Badia, Sandra Franco, Miguel A. Martinez, Javier P. Martinez, Andreas Meyerhans, Francesco Saladini, Maurizio Zazzi, Anna Garbelli, Giovanni Maga, Maurizio Botta

Research output: Contribution to journalArticleResearchpeer-review

46 Citations (Scopus)

Abstract

Targeting a host factor essential for the replication of different viruses but not for the cells offers a higher genetic barrier to the development of resistance, may simplify therapy regimens for coinfections, and facilitates management of emerging viral diseases. DEADbox polypeptide 3 (DDX3) is a human host factor required for the replication of several DNA and RNA viruses, including some of the most challenging human pathogens currently circulating, such as HIV-1, Hepatitis C virus, Dengue virus, and West Nile virus. Herein, we showed for the first time, to our knowledge, that the inhibition of DDX3 by a small molecule could be successfully exploited for the development of a broad spectrum antiviral agent. In addition to the multiple antiviral activities, hit compound 16d retained full activity against drug-resistant HIV-1 strains in the absence of cellular toxicity. Pharmacokinetics and toxicity studies in rats confirmed a good safety profile and bioavailability of 16d. Thus, DDX3 is here validated as a valuable therapeutic target.
Original languageEnglish
Pages (from-to)5388-5393
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number19
DOIs
Publication statusPublished - 10 May 2016

Keywords

  • Broad spectrum antivirals
  • Coinfections
  • DDX3
  • Host factors
  • Resistance

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