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

  • Proc Natl Acad Sci U S A. 2016 May 10;113(19):5388-93. doi: 10.1073/pnas.1522987113.
Annalaura Brai  1 ,  Roberta Fazi  1 ,  Cristina Tintori  1 ,  Claudio Zamperini  1 ,  Francesca Bugli  2 ,  Maurizio Sanguinetti  2 ,  Egidio Stigliano  3 ,  José Esté  4 ,  Roger Badia  4 ,  Sandra Franco  4 ,  Miguel A Martinez  4 ,  Javier P Martinez  5 ,  Andreas Meyerhans  6 ,  Francesco Saladini  7 ,  Maurizio Zazzi  7 ,  Anna Garbelli  8 ,  Giovanni Maga  9 ,  Maurizio Botta  10
Affiliations
  • 1. Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, I-53100 Siena, Italy;
  • 2. Istituto di Microbiologia, Università Cattolica del Sacro Cuore, 00168 Rome, Italy;
  • 3. Institute of Pathological Anatomy, University Hospital A. Gemelli, Catholic University of Sacred Heart, 00168 Rome, Italy;
  • 4. AIDS Research Institute, IrsiCaixa, Hospital Universitari Germans Trias i Pujol, Universitat Autònoma de Barcelona, 08916 Barcelona, Spain;
  • 5. Infection Biology Group, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Parc de Recerca Biomedica Barcelona, 08003 Barcelona, Spain;
  • 6. Infection Biology Group, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Parc de Recerca Biomedica Barcelona, 08003 Barcelona, Spain; Institució Catalana de Recerca i Estudis Avançats, 08010 Barcelona, Spain;
  • 7. Dipartimento di Biotecnologie Mediche, Università degli Studi di Siena, 53100 Siena, Italy;
  • 8. Istituto di Genetica Molecolare, Consiglio Nazionale delle Ricerche (IGM-CNR), 27100 Pavia, Italy;
  • 9. Istituto di Genetica Molecolare, Consiglio Nazionale delle Ricerche (IGM-CNR), 27100 Pavia, Italy; [email protected] [email protected].
  • 10. Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, I-53100 Siena, Italy; Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, PA 19122; Lead Discovery Siena S.r.l., Castelnuovo Berardenga, 53019 Siena, Italy [email protected] [email protected].
PMID: 27118832 DOI: 10.1073/pnas.1522987113
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. DEAD-box 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.

Keywords
DDX3; broad spectrum antivirals; coinfections; host factors; resistance.
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