Abstract
The interaction between the HIV-1 transactivator protein Tat and TAR (transactivation responsive region) RNA, plays a critical role in HIV-1 transcription. Iron(II) supramolecular helicates were evaluated for their in vitro activity to inhibit Tat–TAR RNA interaction using UV melting studies, electrophoretic mobility shift assay, and RNase A footprinting. The results demonstrate that iron(II) supramolecular helicates inhibit Tat-TAR interaction at nanomolar concentrations by binding to TAR RNA. These studies provide a new insight into the biological potential of metallosupramolecular helicates.
Highlights
The trans activation response region (TAR) of RNA (Fig. 1b) represents an attractive target for the inhibition of human imunodeficiency virus type 1 (HIV-1) replication by small molecules
trans activator protein (Tat) binds to TAR RNA at the three-nucleotide pyrimidine bulge and interacts with two base pairs above and below the bulge in the major groove of the TAR RNA molecule[2,3]
Numerous small molecules and peptides that bind three-nucleotide bulges have been synthesized and tested in the past[6,7,8,9,10], but many of these molecules did not have sufficient potency to progress into pharmaceutical development[11]
Summary
Binding of the helicates to the HIV-1 TAR RNA. UV melting studies. It supports the presence of only one major binding site for the helicates on the TAR RNA. Further investigation of these helicates and their new derivatives more selective for TAR RNA in HIV1-infected cellular environments is required for better understanding of their efficacies in HIV-1 therapy which can lead to the discovery of novel and highly potent antivirals
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