2. Academic Validation
  3. Human DDX3 protein is a valuable target to develop broad spectrum antiviral agents

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

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; maga@igm.cnr.it botta.maurizio@gmail.com.
  • 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 maga@igm.cnr.it botta.maurizio@gmail.com.
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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