Human DDX3 protein is a valuable target to develop broad spectrum antiviral agents.
Annalaura BraiRoberta FaziCristina TintoriClaudio ZamperiniFrancesca BugliMaurizio SanguinettiEgidio StiglianoJosé EstéRoger BadiaSandra FrancoMiguel Angel MartinezJavier P MartinezAndreas MeyerhansFrancesco SaladiniMaurizio ZazziAnna GarbelliGiovanni MagaMaurizio BottaPublished in: Proceedings of the National Academy of Sciences of the United States of America (2016)
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.
Keyphrases
- hepatitis c virus
- drug resistant
- endothelial cells
- small molecule
- human immunodeficiency virus
- dengue virus
- induced pluripotent stem cells
- antiretroviral therapy
- hiv positive
- multidrug resistant
- oxidative stress
- pluripotent stem cells
- healthcare
- zika virus
- hiv testing
- sars cov
- drug delivery
- dna methylation
- transcription factor
- mesenchymal stem cells
- south africa
- gene expression
- cell free
- signaling pathway
- copy number
- binding protein
- cancer therapy
- cell death
- cell cycle arrest
- pi k akt
- endoplasmic reticulum stress
- oxide nanoparticles
- circulating tumor cells