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Viral and fungal infections and some cancers may be described as diseases that are characterized by the expression of certain unwanted proteins. They could be termed induced genetic disorders, with induction provided by mutation or infection. A comprehensive method to inactivate injurious genes based on their nucleic acid sequences has the potential to provide effective antiviral and anticancer agents with greatly reduced side effects. We describe a chemical approach to such gene-specific pharmaceutical agents. Our initial efforts have been to develop new chemical reagents that can carry out catalytic destruction of specific mRNA sequences. We chose hydrolysis as a chemical means of destruction, because hydrolysis is compatible with living cells. Our sequence-specific catalytic RNA hydrolysis reagents may be described as functional ribozyme mimics. Reactivity is provided by small-molecule catalysts, such as metal complexes. Specificity is provided by oligonucleotide probes. Here we report initial results on the sequence-specific, hydrolytic cleavage of mRNA from the HIV gag gene, using a ribozyme mimic. The reagent is composed of a terpyridylCu(II) complex for cleavage activity and an oligonucleotide for sequence specificity.

The incorporation of the 2,2′:6′,2′′-terpyridyl (terpy) complex of Cu(II) into a deoxyoligonucleotide has led to a functional mimic of ribozymes. The resulting mimic can cleave target RNA in a sequence-directed manner by a hydrolytic mechanism. Here we describe the synthesis and characterization of four modified nucleoside phosphoramidite reagents (7, 10, 14, and 18) that contain pendant 2,2′-bipyridine or terpy ligands. The ligands are attached either to the nucleobase (7, 10) or to the sugar (14, 18). Nucleobase modification was carried out at the C-5 position of 2′-deoxyuridine (dU). One route to sugar modification was performed by synthesis of 18, a 1′functionalized analog of dU based on 1-[3-deoxy-β-D-psicofuranosyl]uracil. Another route to sugar functionaliztion resulted in 14, a 2′-O-alkyl derivative of adenosine. These modified nucleosides are building blocks for ribozyme mimics. They are designed to deliver hydrolytically active metal complexes across either the major groove (7, 10) or the minor groove (14, 18) of an RNA/DNA duplex.