RNA hydrolysis and inhibition of translation by a Co(III)–cyclen complex

Abstract

Metal ion-chelator catalysts based on main-group, lanthanide, or transition metal complexes have been developed as nonenzymatic alternatives for the hydrolysis of the phosphodiester bonds in DNA and RNA. Cobalt (III), with its high-charge density, is known for its ability to hydrolyze phosphodiesters with rate constants as high as 2 x 10(-4) s(-1). We have developed a kinetically inert Co(III)-cyclen-based complex, Co(III)-cycmmb that is very potent in inhibiting the translation of RNA into protein. Contact time as short as 10 min is sufficient to achieve the complete inhibition of the translation of a concentrated luciferase RNA solution into the enzyme in a cell-free translation system. The inhibition appears to proceed through two pathways. The first pathway involves the kinetic or substitutional inertness of Co(III) for the RNA template at short contact times. This interaction is mediated through the kinetic inertness of Co(III) for the phosphate groups of the nucleotides, as well as coordination of Co(III) to the nitrogenous bases. The second pathway occurs at longer contact times and is mediated by the hydrolysis of the phosphodiester backbone. This report represents the first demonstrated use of a metal-chelate complex to achieve the inhibition of the translation of RNA into protein. This Co(III) system can be useful in its present nonsequence-specific form as a novel viral decontamination agent. When functionalized to recognize specific nucleic acid sequences, such a system could potentially be used in gene-silencing applications as an alternative to standard antisense or RNAi technologies.