Binding of a Designed Anti‐Cancer Drug to the Central Cavity of an RNA Three‐Way Junction

Abstract

Getting to the heart of it: Co-crystallization of an RNA three-way junction with a cylindrical di-iron(II)-based anti-cancer drug (green) results in π-stacking interactions between the cylinder and the central base pairs of the RNA structure. The shape, size, and cationic nature of the cylinder were found to be responsible for this perfect fit. Native gel electrophoresis studies confirmed stabilization of the RNA three-way junction by the iron(II) cylinder.

Covalent and non-covalent binding of metal complexes to RNA

“…Freisinger, Hannon, Spingler, Sigel and coworkers recently reported the crystal structure of a dinuclear Fe(II) cylinder with a palindromic hexanucleotide RNA sequence (Fig. 10b) [41]. The structure contains exclusively the M enantiomer of the cylinder, and shows one cylinder sitting in the heart of a three-way junction RNA, to optimize π-stacking interactions between the phenylene rings and the RNA bases (Fig.…”

“…Additional cylinder molecules are located at the termini of the three arms of the junctions. This structure represents the first crystallographic example of a designed metal complex bound to RNA [41]. The authors also explored the ability of the cylinder to induce RNA three-way junction formation in solution.…”

“…In the sections below some recent advances in non-covalent binding of metal complexes to RNA are described and discussed. In particular, the following aspects are covered: (i) the use of metal complexes as RNA structural probes [40,107,108] (Section 4.1); (ii) the structure of a metal complex interacting with an RNA three-way junction [41] (Section 4.2); (iii) the development of metal complexes targeting viral RNA [109][110][111][112] (Section 4.3); (iv) the combination of metal complexes with small RNA-binding organic molecules (Section 4.4) [113][114][115][116][117]; (v) the use of RNA-targeting metal complexes in cell imaging [42,43,[118][119][120][121] (Section 4.5); (vi) comparison between DNA and RNA binding properties of some metal complexes [122][123][124][125] (Section 4.6); (vii) the RNA binding ability of some metal surfactants and metal polymers [126][127][128][129] (Section 4.7) and (viii) the binding of metal complexes to RNA triplexes [46,[130][131][132][133] (Section 4.8).…”

“…Surprisingly, the RNA binding abilities of small metal complexes, which can bind to RNA both covalently and non-covalently, have been much less explored [3,39,40]. However, a few recently published papers highlight the renewed interest of the scientific community for this topic [41][42][43][44][45][46][47].…”

Neutral discrete metal–organic cyclic architectures: Opportunities for structural features and properties in confined spaces

“…Hannon's group focused on the design of saturated and unsaturated metal helicates that offer the possibility of a direct interaction between the metal center and the central cavity of a DNA and RNA molecule [130][131][132][133][134]. One of their studies describes the preparation of three isomeric dinuclear unsaturated ruthenium(II) complexes (trans/trans-[Ru 2 Cl 4 L 2 ] (9a), trans/cis-[Ru 2 Cl 4 L 2 ] (9b) and cis/cis [Ru 2 Cl 4 L 2 ] (9c)) each with a different double-stranded supramolecular architecture and information related to their activity in cell lines [135].…”