Helix-stabilizing compounds CC-1065 and U-71,184 bind to RNA-DNA and DNA-DNA duplexes containing modified internucleotide linkages and stabilize duplexes against thermal melting.
CC-1065 and U-71,184 bind and hyperstabilize DNA duplexes, but little is known about their effects on nucleic acid duplexes of different structure. A 20 mer DNA sequence (5'-TTACTTCAGTTATGAGACCA) containing a drug binding sequence (5'-AGTTA) was selected as the target sequence, and this was duplexed with complementary antisense sequences containing phosphodiester (PO), phosphorothioate (PS), and methylphosphonate (MP) bonds. The duplexes containing PO or PS bound 2 CC-1065 molecules per duplex, presumably at both the target site and at a lower affinity site (5'-AGTAA) on the antisense strand. The duplex containing MP bound only 1 CC-1065, and all duplexes bound only 1 U-71,184. Both CC-1065 and U-71,184 bound to 20 mer duplexes comprised of oligo(dA)-oligo(dT) (2.5 and 2 drugs per duplex, respectively) and poly(rA)-oligo(dT) (1 drug per 20 base pairs). CC-1065 also bound to duplexes between the PO- or PS-based antisense structures and a complementary synthetic 20 mer RNA sequence, with about 1 drug per duplex in each case. CC-1065 increased the Tm for the 20 mer DNA duplexes 17 to 29 degrees C, and the corresponding values for U-71,184 ranged from 7 to 19 degrees C. CC-1065 raised the Tm of oligo(dA)-oligo(dT) and poly(rA)-oligo(dT) 29 degrees C. U71,184 increased the Tm for oligo(dA)-oligo(dT) 30 degrees C but did not significantly elevate the Tm for the corresponding RNA-DNA duplex. The results show that CC-1065 and U-71,184 are capable of binding and stabilizing a variety of nucleic acid duplexes. These agents or their analogs may become useful ligands for antisense oligonucleotide applications.
Kim
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Department of Veterinary Pathology, School of Veterinary Medicine, Louisiana State University (LSU), Baton Rouge 70803, USA.
Shih
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Cho
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Swenson
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D000970:Antineoplastic Agents / Q000494:pharmacology*; D001483:Base Sequence; D001665:Binding Sites; D004247:DNA / Q000737:chemistry* / Q000378:metabolism; D000080890:Duocarmycins; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D007933:Leucomycins / Q000737:chemistry / Q000494:pharmacology*; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009690:Nucleic Acid Conformation / Q000187:drug effects*; D009692:Nucleic Acid Heteroduplexes / Q000737:chemistry* / Q000378:metabolism; D009838:Oligodeoxyribonucleotides / Q000737:chemistry*; D016376:Oligonucleotides, Antisense / Q000737:chemistry*; D011067:Poly dA-dT / Q000737:chemistry; D012313:RNA / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013873:Thionucleotides
D000970:Antineoplastic Agents; D000080890:Duocarmycins; D007211:Indoles; D007933:Leucomycins; D009692:Nucleic Acid Heteroduplexes; D009838:Oligodeoxyribonucleotides; D016376:Oligonucleotides, Antisense; D013873:Thionucleotides; C016023:oligo(dA-dT); C054483:U 71184; D011067:Poly dA-dT; D012313:RNA; C018782:CC 1065; D004247:DNA