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.

Targeting structural features of viral genomes with a nano-sized supramolecular drug

“…42,43 It is also unique in threading through an RNA cavity, interacting with all of the internal structure. These cylinders also bind bulge structures in RNA, prevent TAT protein from recognizing the binding site in the TAR sequence of HIV 35,44 and arrest HIV replication in mammalian cells. 35 The strong evidence of binding and in-cell efficacy, makes this an ideal test-bed to investigate whether molecular dynamics simulations can identify the processes that underpin the kinetics of targeting highly exible RNA strands.…”

“…These cylinders also bind bulge structures in RNA, prevent TAT protein from recognizing the binding site in the TAR sequence of HIV 35,44 and arrest HIV replication in mammalian cells. 35 The strong evidence of binding and in-cell efficacy, makes this an ideal test-bed to investigate whether molecular dynamics simulations can identify the processes that underpin the kinetics of targeting highly exible RNA strands. At the same time, it provides a suitable challenging size of drug, and one with large, nanoscale, 3dimensional molecular surfaces whose match and strong binding to the 3D shape of RNA structural motifs should collapse the RNA's conformational landscape to a nonfunctional (impotent) state.…”

“…The nano-scale drugs studied are supramolecular cylinders, which not only have unprecedented RNA bulge-binding ability but are the rst in class of metallo-supramolecular architectures to show potent anti-viral activity in cellular assays. 35 There is a growing interest in the application of metallo-supramolecular architectures in biology. [36][37][38][39][40][41]…”

Supramolecular cylinders target bulge structures in the 5’ UTR of the RNA genome of SARS-CoV-2 and inhibit viral replication

“…We have characterized the binding of cylinders in an RNA 3-way junction [32] by crystallography (Fig. 1C) and showed analogous binding in an RNA bulge structure [33,34]. Furthermore, we demonstrated cylinder binding to an RNA 3-base bulge in the TAR region of the HIV-1 genome (located in its UTR), that prevented HIV-1 replication [34].…”

A Pt(II)‐based Hexagonal Ionic Supramolecular Coordination Complex and its DNA Interactions.

“…In this regard, it is especially interesting to examine the interaction of metal‐based supramolecular entities and DNA. This specific biological application of SCCs has been promoted by Hannon, Therrien, Sleiman, Mao, Chi, and others . The motivation to study extent of interaction between SCCs and DNA probably stems from the knowledge that cisplatin and other Pt(II) based inorganic complexes coordinate with purine bases in DNA leading to death of cancer cells .…”