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Metallo supramolecular cylinders inhibit HIV-1 TAR-TAT complex formation and viral replication in cellulo.

ABSTRACT: Shape-selective recognition of nucleic acid structures by supramolecular drugs offers the potential to treat disease. The Trans Activation Response (TAR) region is a region of high secondary structure within the human immunodeficiency virus-1 (HIV-1) RNA that complexes with the virus-encoded Transactivator protein (TAT) and regulates viral transcription. Herein, we explore different metallo-supramolecular triple stranded helicates (cylinders) that target the TAR bulge motif and inhibit the formation of TAR-TAT complexes and HIV infection. Cylinders that incorporate Ni(II) and Ru(II) showed the most potent anti-viral activity with limited evidence of cellular cytotoxicity. These metallo-supramolecular compounds provide an exciting avenue for developing a new class of anti-viral agents.

SUBMITTER: Cardo L

PROVIDER: S-EPMC6127258 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Metallo supramolecular cylinders inhibit HIV-1 TAR-TAT complex formation and viral replication in cellulo.

Cardo Lucia L Nawroth Isabel I Cail Peter J PJ McKeating Jane A JA Hannon Michael J MJ

Scientific reports 20180906 1

Shape-selective recognition of nucleic acid structures by supramolecular drugs offers the potential to treat disease. The Trans Activation Response (TAR) region is a region of high secondary structure within the human immunodeficiency virus-1 (HIV-1) RNA that complexes with the virus-encoded Transactivator protein (TAT) and regulates viral transcription. Herein, we explore different metallo-supramolecular triple stranded helicates (cylinders) that target the TAR bulge motif and inhibit the forma ...[more]

PMID: 30190568

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Project description:The HIV-1 Tat protein interacts with TAR RNA and recruits CDK9/cyclin T1 and other host factors to induce HIV-1 transcription. Thus, Tat-TAR RNA interaction, which is unique for HIV-1, represents an attractive target for anti-HIV-1 therapeutics. To target Tat-TAR RNA interaction, we used a crystal structure of acetylpromazine bound to the bulge of TAR RNA, to dock compounds from the Enamine database containing over two million individual compounds. The docking procedure identified 173 compounds that were further analyzed for the inhibition of HIV-1 infection. The top ten inhibitory compounds with IC50 ≤ 6 µM were selected and the three least toxic compounds, T6780107 (IC50 = 2.97 μM), T0516-4834 (IC50 = 0.2 μM) and T5628834 (IC50 = 3.46 μM), were further tested for HIV-1 transcription inhibition. Only the T0516-4834 compound showed selective inhibition of Tat-induced HIV-1 transcription, whereas the T6780107 compound inhibited equally basal and Tat-induced transcription and the T5628834 compound only inhibited basal HIV-1 transcription. The compounds were tested for the inhibition of translation and showed minimal (<25%) effect. The T0516-4834 compound also showed the strongest inhibition of HIV-1 RNA expression and p24 production in CEM T cells and peripheral blood mononuclear cells infected with HIV-1 IIIB. Of the three compounds, only the T0516-4834 compound significantly disrupted Tat-TAR RNA interaction. Additionally, of the three tested compounds, T5628834 and, to a lesser extent, T0516-4834 disrupted Tat-CDK9/cyclin T1 interaction. None of the three compounds showed significant inhibition of the cellular CDK9 and cyclin T1 levels. In silico modelling showed that the T0516-4834 compound interacted with TAR RNA by binding to the bulge formed by U23, U25, C39, G26,C39 and U40 residues. Taken together, our study identified a novel benzoxazole compound that disrupted Tat-TAR RNA interaction and inhibited Tat-induced transcription and HIV-1 infection, suggesting that this compound might serve as a new lead for anti-HIV-1 therapeutics.

Project description:HIV-1 remains a global health concern and to date, nearly 38 million people are living with HIV. The complexity of HIV-1 pathogenesis and its subsequent prevalence is influenced by several factors including the HIV-1 subtype. HIV-1 subtype variation extends to sequence variation in the amino acids of the HIV-1 viral proteins. Of particular interest is the transactivation of transcription (Tat) protein due to its key function in viral transcription. The Tat protein predominantly functions by binding to the transactivation response (TAR) RNA element to activate HIV-1 transcriptional elongation. Subtype-specific Tat protein sequence variation influences Tat-TAR binding affinity. Despite several studies investigating Tat-TAR binding, it is not clear which regions of the Tat protein and/or individual Tat amino acid residues may contribute to TAR binding affinity. We, therefore, conducted a scoping review on studies investigating Tat-TAR binding. We aimed to synthesize the published data to determine (1) the regions of the Tat protein that may be involved in TAR binding, (2) key Tat amino acids involved in TAR binding and (3) if Tat subtype-specific variation influences TAR binding. A total of thirteen studies met our inclusion criteria and the key findings were that (1) both N-terminal and C-terminal amino acids outside the basic domain (47-59) may be important in increasing Tat-TAR binding affinity, (2) substitution of the amino acids Lysine and Arginine (47-59) resulted in a reduction in binding affinity to TAR, and (3) none of the included studies have investigated Tat subtype-specific substitutions and therefore no commentary could be made regarding which subtype may have a higher Tat-TAR binding affinity. Future studies investigating Tat-TAR binding should therefore use full-length Tat proteins and compare subtype-specific variations. Studies of such a nature may help explain why we see differential pathogenesis and prevalence when comparing HIV-1 subtypes.

Dataset Information

Metallo supramolecular cylinders inhibit HIV-1 TAR-TAT complex formation and viral replication in cellulo.

Publications

Metallo supramolecular cylinders inhibit HIV-1 TAR-TAT complex formation and viral replication in cellulo.

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