The search for structure-specific nucleic acid-interactive drugs: Effects of compound structure on RNA versus DNA interaction strength

Abstract

The RNA genomes of a number of pathogenic RNA viruses, such as HIV-1, have extensive folded conformations with imperfect A-form duplexes that are essential for virus function and could serve as targets for structure-specific antiviral drugs. As an initial step in the discovery of such drugs, the interactions with RNA of a wide variety of compounds, which are known to bind to DNA in the minor groove, by classical or by threading intercalation, have been evaluated by thermal melting and viscometric analyses. The corresponding sequence RNA and DNA polymers, poly(A).poly(U) and poly(dA).poly(dT), were used as test systems for analysis of RNA binding strength and selectivity. Compounds that bind exclusively in the minor groove in AT sequences of DNA (e.g., netropsin, distamycin, and a zinc porphyrin derivative) do not have significant interactions with RNA. Compounds that bind in the minor grove in AT sequences of DNA but have other favorable interactions in GC sequences of DNA (e.q., Hoechst 33258, DAPI, and other aromatic diamidines) can have very strong RNA interactions. A group of classical intercalators and a group of intercalators with unfused aromatic ring systems contain compounds that intercalate and have strong interactions with RNA. At this time, no clear pattern of molecular structure that favors RNA over DNA interactions for intercalators has emerged. Compounds that bind to DNA by threading intercalation generally bind to RNA by the same mode, but none of the threading intercalators tested to date have shown selective interactions with RNA.