title: Sequence-specific base pair mimics are efficient topoisomerase IB inhibitors.
abstract: Topoisomerase IB controls DNA topology by cleaving DNA transiently. This property is used by inhibitors, such as camptothecin, that stabilize, by inhibiting the religation step, the cleavage complex, in which the enzyme is covalently attached to the 3'-phosphate of the cleaved DNA strand. These drugs are used in clinics as antitumor agents. Because three-dimensional structural studies have shown that camptothecin derivatives act as base pair mimics and intercalate between two base pairs in the ternary DNA-topoisomerase-inhibitor complex, we hypothesized that base pairs mimics could act like campthotecin and inhibit the religation reaction after the formation of the topoisomerase I-DNA cleavage complex. We show here that three base pair mimics, nucleobases analogues of the aminophenyl-thiazole family, once targeted specifically to a DNA sequence were potent topoisomerase IB inhibitors. The targeting was achieved through covalent linkage to a sequence-specific DNA ligand, a triplex-forming oligonucleotide, and was necessary to position and keep the nucleobase analogue in the cleavage complex. In the absence of triplex formation, only a weak binding to the DNA and topoisomerase I-mediated DNA cleavage was observed. The three compounds were equally active once conjugated, implying that the intercalation of the nucleobase upon triplex formation is the essential feature for the inhibition activity.
authors: CNRS UMR7196, Muséum National d'Histoire Naturelle, 43 rue Cuvier, 75005 Paris, France.
authors: Pierre
authors: P
authors: Vekhoff
authors: Maria
authors: M
authors: Duca
authors: Dominique
authors: D
authors: Guianvarc'h
authors: Rachid
authors: R
authors: Benhida
authors: Paola B
authors: PB
authors: Arimondo
mesh_terms: D020029:Base Pairing / Q000187:drug effects / Q000235:genetics; D001483:Base Sequence; D004247:DNA / Q000138:chemical synthesis / Q000494:pharmacology*; D004249:DNA Damage / Q000187:drug effects / Q000235:genetics; D018983:DNA Footprinting / Q000379:methods; D004264:DNA Topoisomerases, Type I / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism; D003850:Deoxyribonuclease I / Q000737:chemistry / Q000235:genetics; D018390:Gene Targeting / Q000379:methods; D018716:Molecular Mimicry / Q000235:genetics; D008969:Molecular Sequence Data; D009690:Nucleic Acid Conformation / Q000187:drug effects; D009692:Nucleic Acid Heteroduplexes / Q000138:chemical synthesis / Q000494:pharmacology*; D059004:Topoisomerase I Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*
chemical_list: D004268:DNA-Binding Proteins; D009692:Nucleic Acid Heteroduplexes; D059004:Topoisomerase I Inhibitors; C051802:triplex DNA; D004247:DNA; D003850:Deoxyribonuclease I; D004264:DNA Topoisomerases, Type I