TY - JOUR
T1 - Human DDX3 protein is a valuable target to develop broad spectrum antiviral agents
AU - Brai, Annalaura
AU - Fazi, Roberta
AU - Tintori, Cristina
AU - Zamperini, Claudio
AU - Bugli, Francesca
AU - Sanguinetti, Maurizio
AU - Stigliano, Egidio
AU - Esté, José
AU - Badia, Roger
AU - Franco, Sandra
AU - Martinez, Miguel A.
AU - Martinez, Javier P.
AU - Meyerhans, Andreas
AU - Saladini, Francesco
AU - Zazzi, Maurizio
AU - Garbelli, Anna
AU - Maga, Giovanni
AU - Botta, Maurizio
PY - 2016/5/10
Y1 - 2016/5/10
N2 - 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.
AB - 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.
KW - Broad spectrum antivirals
KW - Coinfections
KW - DDX3
KW - Host factors
KW - Resistance
U2 - 10.1073/pnas.1522987113
DO - 10.1073/pnas.1522987113
M3 - Article
SN - 0027-8424
VL - 113
SP - 5388
EP - 5393
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 19
ER -
