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.

Brai, A., Fazi, R., Tintori, C., Zamperini, C., Bugli, F., Sanguinetti, M., Stigliano, E., Esté, J., Badia, R., Franco, S., Martinez, M. A., Martinez, J. P., Meyerhans, A., Saladini, F., Zazzi, M., Garbelli, A., Maga, G., Botta, M., Human DDX3 protein is a valuable target to develop broad spectrum antiviral agents, <<PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA>>, 2016; 113 (19): 5388-5393. [doi:10.1073/pnas.1522987113] [http://hdl.handle.net/10807/75272]

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

Bugli, Francesca;Sanguinetti, Maurizio;Stigliano, Egidio;
2016

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.
Inglese
Brai, A., Fazi, R., Tintori, C., Zamperini, C., Bugli, F., Sanguinetti, M., Stigliano, E., Esté, J., Badia, R., Franco, S., Martinez, M. A., Martinez, J. P., Meyerhans, A., Saladini, F., Zazzi, M., Garbelli, A., Maga, G., Botta, M., Human DDX3 protein is a valuable target to develop broad spectrum antiviral agents, <>, 2016; 113 (19): 5388-5393. [doi:10.1073/pnas.1522987113] [http://hdl.handle.net/10807/75272]
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