1. Human DDX3 protein is a valuable target to develop broad spectrum antiviral agents.
- Author
-
Brai A, Fazi R, Tintori C, Zamperini C, Bugli F, Sanguinetti M, Stigliano E, Esté J, Badia R, Franco S, Martinez MA, Martinez JP, Meyerhans A, Saladini F, Zazzi M, Garbelli A, Maga G, and Botta M
- Subjects
- Drug Design, Enzyme Inhibitors, Antiviral Agents administration & dosage, DEAD-box RNA Helicases antagonists & inhibitors, DEAD-box RNA Helicases metabolism, Molecular Targeted Therapy methods, Virus Replication drug effects, Virus Replication physiology
- 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.
- Published
- 2016
- Full Text
- View/download PDF