Helix-Stabilizing Agent, CC-1065, Enhances Suppression of Translation by an Antisense Oligodeoxynucleotide

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Abstract
The antitumor antibiotic CC-1065 is known to bind at selected sequences in the minor groove of duplex nucleic acids and to hyperstabilize the duplexes against thermal melting. These properties suggested that CC-1065 may enhance translation inhibition by antisense oligonucleotides directed against a specific mRNA. A 585 bp mRNA transcript containing the equine infectious anemia virus (EIAV) S2 gene and a portion of the env gene was prepared. Also, a complementary 20 mer antisense oligodeoxynucleotide (5′-TGTTGGGTAATAGGGGTTGA-3′) was prepared against a target sequence in the mRNA located near the translational initiation sites of the overlapping S2 and env genes. The center of the target sequence had an expected CC-1065 recognition sequence (5′-UAUUA-3′). Translation in the presence of CC-1065 and antisense was markedly suppressed compared with that of antisense alone. Addition of a sense 20 mer strand, with or without CC-1065, had little or no effect on translation. CC-1065 and related compounds may be useful as ligands for enhancing the stability of sense-antisense duplexes and for promoting the inhibition of translation by antisense oligonucleotides.