The human ATPase/RNA helicase X-linked DEAD-box polypeptide 3 (DDX3X) emerged as a novel therapeutic target in the fight against both infectious diseases and cancer. Herein, a new family of DDX3X inhibitors was designed, synthesized, and tested for its inhibitory action on the ATPase activity of the enzyme. The potential use of the most promising derivatives it has been investigated by evaluating their anti-HIV-1 effects, revealing inhibitory activities in the low micromolar range. A preliminary ADME analysis demonstrated high metabolic stability and good aqueous solubility. The promising biological profile, together with the suitable in vitro pharmacokinetic properties, make these novel compounds a very good starting point for further development.
In the absence of effective drugs
or vaccines for the treatment
of the five Dengue Virus serotypes, the search for novel antiviral
drugs is of primary importance for the scientific community. In this
context, drug repurposing represents the most used strategy; however,
the study of host targets is now attracting attention since it allows
identification of broad-spectrum drugs endowed with high genetic barrier.
In the last ten years our research group identified several small
molecules DDX3X inhibitors and proved their efficacy against different
viruses including novel emerging ones. Herein, starting from a screening
of our compounds, we designed and synthesized novel derivatives with
potent activity and high selectivity. Finally, we synthesized a fluorescent
inhibitor that allowed us to study DDX3X cellular localization during
DENV infection in vitro. Immunofluorescence analysis
showed that our inhibitor colocalized with DDX3X, promoting the reduction
of infected cells and recovering the number of viable cells.
Removal of ribonucleotides (rNMPs) incorporated into the genome by the ribonucleotide excision repair (RER) is essential to avoid genetic instability. In eukaryotes, the RNaseH2 is the only known enzyme able to incise 5′ of the rNMP, starting the RER process, which is subsequently carried out by replicative DNA polymerases (Pols) δ or ϵ, together with Flap endonuclease 1 (Fen-1) and DNA ligase 1. Here, we show that the DEAD-box RNA helicase DDX3X has RNaseH2-like activity and can support fully reconstituted in vitro RER reactions, not only with Pol δ but also with the repair Pols β and λ. Silencing of DDX3X causes accumulation of rNMPs in the cellular genome. These results support the existence of alternative RER pathways conferring high flexibility to human cells in responding to the threat posed by rNMPs incorporation.
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