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Iron(II) supramolecular helicates interfere with the HIV-1 Tat-TAR RNA interaction critical for viral replication.

Malina J, Hannon MJ, Brabec V - Sci Rep (2016)

Bottom Line: The interaction between the HIV-1 transactivator protein Tat and TAR (transactivation responsive region) RNA, plays a critical role in HIV-1 transcription.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.

View Article: PubMed Central - PubMed

Affiliation: Institute of Biophysics, Academy of Sciences of the Czech Republic, v.v.i., Kralovopolska 135, CZ-61265 Brno, Czech Republic.

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.

No MeSH data available.


Structures of helicates, RNA nucleotide sequences and amino acid sequence of the ADP-1 polypeptide.(a) Structures of the ligand L and the tetracataionic triple helicate M-[Fe2L3]4+ formed from that ligand [adapted from Protein Data Bank (PDB) file 2ET0]. (b) Sequences of the TAR RNA, containing residues 18–44 of HIV-1 mRNA and two additional G·C base pairs, and the fully matched RNA duplex. (c) The sequence of the ADP-1 polypeptide carrying the minimal RNA recognition region of the Tat protein (residues 37–72) and closely mimicking Tat binding specificity.
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f1: Structures of helicates, RNA nucleotide sequences and amino acid sequence of the ADP-1 polypeptide.(a) Structures of the ligand L and the tetracataionic triple helicate M-[Fe2L3]4+ formed from that ligand [adapted from Protein Data Bank (PDB) file 2ET0]. (b) Sequences of the TAR RNA, containing residues 18–44 of HIV-1 mRNA and two additional G·C base pairs, and the fully matched RNA duplex. (c) The sequence of the ADP-1 polypeptide carrying the minimal RNA recognition region of the Tat protein (residues 37–72) and closely mimicking Tat binding specificity.

Mentions: 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. The binding of the viral trans activator protein (Tat) to the TAR RNA is an essential step in the HIV-1 replication cycle. Therefore, the blockage of the Tat-TAR interaction is a potential route for AIDS chemotherapy. Compounds that bind to TAR RNA, and prevent binding by Tat, could disrupt processive transcription and thereby inhibit viral growth1.


Iron(II) supramolecular helicates interfere with the HIV-1 Tat-TAR RNA interaction critical for viral replication.

Malina J, Hannon MJ, Brabec V - Sci Rep (2016)

Structures of helicates, RNA nucleotide sequences and amino acid sequence of the ADP-1 polypeptide.(a) Structures of the ligand L and the tetracataionic triple helicate M-[Fe2L3]4+ formed from that ligand [adapted from Protein Data Bank (PDB) file 2ET0]. (b) Sequences of the TAR RNA, containing residues 18–44 of HIV-1 mRNA and two additional G·C base pairs, and the fully matched RNA duplex. (c) The sequence of the ADP-1 polypeptide carrying the minimal RNA recognition region of the Tat protein (residues 37–72) and closely mimicking Tat binding specificity.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4940744&req=5

f1: Structures of helicates, RNA nucleotide sequences and amino acid sequence of the ADP-1 polypeptide.(a) Structures of the ligand L and the tetracataionic triple helicate M-[Fe2L3]4+ formed from that ligand [adapted from Protein Data Bank (PDB) file 2ET0]. (b) Sequences of the TAR RNA, containing residues 18–44 of HIV-1 mRNA and two additional G·C base pairs, and the fully matched RNA duplex. (c) The sequence of the ADP-1 polypeptide carrying the minimal RNA recognition region of the Tat protein (residues 37–72) and closely mimicking Tat binding specificity.
Mentions: 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. The binding of the viral trans activator protein (Tat) to the TAR RNA is an essential step in the HIV-1 replication cycle. Therefore, the blockage of the Tat-TAR interaction is a potential route for AIDS chemotherapy. Compounds that bind to TAR RNA, and prevent binding by Tat, could disrupt processive transcription and thereby inhibit viral growth1.

Bottom Line: The interaction between the HIV-1 transactivator protein Tat and TAR (transactivation responsive region) RNA, plays a critical role in HIV-1 transcription.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.

View Article: PubMed Central - PubMed

Affiliation: Institute of Biophysics, Academy of Sciences of the Czech Republic, v.v.i., Kralovopolska 135, CZ-61265 Brno, Czech Republic.

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.

No MeSH data available.