RNA-selective modification by a platinum(II) complex conjugated to amino- and guanidinoglycosides.

Binding of the anticancer drug cisplatin (cis-Pt) to nucleic acids is believed to favor DNA over RNA. Covalent modification of DNA produces intrastrand cross-links (at GpG, ApG, and GpNpG; N=A, C, G, or T), and interstrand cross-links (at GG). Cisplatin reacts with other cellular components including proteins, phospholipids, and small molecules. To enhance DNA targeting, numerous conjugates have been prepared in which the cis-Pt moiety has been tethered to high-affinity nucleic acid ligands (for example, acridine, ethidium bromide, peptides, and short oligonucleotides). As part of our program aimed at advancing RNA as a drug target, we have become interested in devising methods to “reverse” the nucleic acid selectivity of cis-Pt. Since RNA–protein complexes serve key functions in the life cycle of many retroviruses, RNA-selective delivery of reactive Pt complexes may provide a novel mechanism for the inactivation of pathogen-specific RNA. HIV-1 replication is critically dependent on the nuclear export of intron-containing viral RNA by the Rev protein. The high-affinity Rev binding site within the Rev response element (RRE) is located at a G-rich bulge that is present in the minimized construct RRE JW shown in Figure 1. Rev–