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

Lucia Cardo,Isabel Nawroth,Peter J Cail,Michael J Hannon,Jane A Mckeating

doi:10.1038/s41598-018-31513-3

Lucia Cardo, Isabel Nawroth + Show 3 more

Open Access

https://doi.org/10.1038/s41598-018-31513-3

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Journal: Scientific Reports	Publication Date: Sep 6, 2018
Citations: 24	License type: open-access

Affiliation: University of Birmingham, University of Oxford

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.

Highlights

Ribonucleic acid (RNA) is involved in a wide range of biological events, mediating the processing of genetic information from DNA to proteins, as structural components of many ribonucleoproteins and as non-coding elements with a variety of gene regulatory functions[1,2]
The retrovirus human immunodeficiency virus type 1 (HIV-1) encodes a Trans Activation Response (TAR) RNA element that comprises a conserved 59-nucleotide stem-loop structure located within the 5′ end of the transcribed viral mRNA (Fig. 1a) in the long terminal repeat (LTR)
The highly conserved HIV TAR motif provides an attractive target for the design of small molecules that inhibit TAR-transactivator protein (TAT) complex formation; to date there has been a paucity of agents targeting this step in the viral life cycle

Summary

Introduction

Ribonucleic acid (RNA) is involved in a wide range of biological events, mediating the processing of genetic information from DNA to proteins, as structural components of many ribonucleoproteins and as non-coding elements with a variety of gene regulatory functions[1,2]. We address these challenges and demonstrate that alternative metal containing supramolecular cylinders bind TAR RNA and reduce ADP-1 interaction(s) and importantly inhibit HIV replication in cell based systems with no significant toxicity.

Results

Conclusion