Human DDX3 protein is a valuable target to develop broad spectrum antiviral agents.
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.
Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, I-53100 Siena, Italy;
Annalaura
A
Brai
Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, I-53100 Siena, Italy;
Roberta
R
Fazi
Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, I-53100 Siena, Italy;
Cristina
C
Tintori
Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, I-53100 Siena, Italy;
Claudio
C
Zamperini
Istituto di Microbiologia, Università Cattolica del Sacro Cuore, 00168 Rome, Italy;
Francesca
F
Bugli
Istituto di Microbiologia, Università Cattolica del Sacro Cuore, 00168 Rome, Italy;
Maurizio
M
Sanguinetti
Institute of Pathological Anatomy, University Hospital A. Gemelli, Catholic University of Sacred Heart, 00168 Rome, Italy;
Egidio
E
Stigliano
AIDS Research Institute, IrsiCaixa, Hospital Universitari Germans Trias i Pujol, Universitat Autònoma de Barcelona, 08916 Barcelona, Spain;
José
J
Esté
AIDS Research Institute, IrsiCaixa, Hospital Universitari Germans Trias i Pujol, Universitat Autònoma de Barcelona, 08916 Barcelona, Spain;
Roger
R
Badia
AIDS Research Institute, IrsiCaixa, Hospital Universitari Germans Trias i Pujol, Universitat Autònoma de Barcelona, 08916 Barcelona, Spain;
Sandra
S
Franco
AIDS Research Institute, IrsiCaixa, Hospital Universitari Germans Trias i Pujol, Universitat Autònoma de Barcelona, 08916 Barcelona, Spain;
Miguel A
0000-0002-6681-4950
MA
Martinez
Infection Biology Group, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Parc de Recerca Biomedica Barcelona, 08003 Barcelona, Spain;
Javier P
JP
Martinez
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;
Andreas
A
Meyerhans
Dipartimento di Biotecnologie Mediche, Università degli Studi di Siena, 53100 Siena, Italy;
Francesco
F
Saladini
Dipartimento di Biotecnologie Mediche, Università degli Studi di Siena, 53100 Siena, Italy;
Maurizio
M
Zazzi
Istituto di Genetica Molecolare, Consiglio Nazionale delle Ricerche (IGM-CNR), 27100 Pavia, Italy;
Anna
A
Garbelli
Istituto di Genetica Molecolare, Consiglio Nazionale delle Ricerche (IGM-CNR), 27100 Pavia, Italy; maga@igm.cnr.it botta.maurizio@gmail.com.
Giovanni
0000-0001-8092-1552
G
Maga
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.
Maurizio
M
Botta
D000998:Antiviral Agents / Q000008:administration & dosage*; D053487:DEAD-box RNA Helicases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D015195:Drug Design; D004791:Enzyme Inhibitors; D058990:Molecular Targeted Therapy / Q000379:methods*; D014779:Virus Replication / Q000187:drug effects* / Q000502:physiology*
D000998:Antiviral Agents; D004791:Enzyme Inhibitors; C119332:DDX3X protein, human; D053487:DEAD-box RNA Helicases
DDX3; broad spectrum antivirals; coinfections; host factors; resistance