Structure/nuclease activity relationships of DNA cleavers based on cationic metalloporphyrin-oligonucleotide conjugates.
The covalent attachment of a managanese-tris(methylpyridiniumyl)porphyrin entity to an antisense oligonucleotide allowed sequence-selective oxidative cleavage of DNA when the metalloporphyrin was activated by potassium monopersulfate (KHSO5). We prepared several structurally modified metallo-porphyrin-oligonucleotide conjugates in order to find out the most efficient compound for in vitro DNA cleavage. The nature and the length of the tether were modulated, the metalloporphyrin entity was modified (metal, ligand), and different ways of activation of the metalloporphyrin were assayed. We noticed that the location of the peptidic bond within the linker could greatly affect the cleavage efficiency of the different conjugates. We showed that the most efficient conjugate for oxidative DNA cleavage was a manganese tetracationic porphyrin-oligonucleotide compound. When the metalloporphyrin moiety was activated by a reducing agent in the presence of molecular oxygen, DNA cleavage was efficient at suitable concentrations of the reducing agent, in order to avoid the reduction of the activated DNA cleaver, a putative high-valent metal-oxo species, by the excess of reducing agent.
Mestre
B
B
Laboratoire de Chimie de Coordination du CNRS, Toulouse, France.
Jakobs
A
A
Pratviel
G
G
Meunier
B
B
D001483:Base Sequence; D002412:Cations; D004249:DNA Damage; D004277:DNA, Single-Stranded / Q000378:metabolism; D004279:DNA, Viral / Q000378:metabolism*; D003851:Deoxyribonucleases / Q000737:chemistry / Q000378:metabolism; D004229:Dithiothreitol / Q000494:pharmacology; D015757:Genes, rev; D015756:Genes, tat; D015497:HIV-1 / Q000235:genetics*; D017895:Manganese Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*; D008665:Metalloporphyrins / Q000737:chemistry / Q000378:metabolism*; D008969:Molecular Sequence Data; D015394:Molecular Structure; D016376:Oligonucleotides, Antisense / Q000737:chemistry / Q000378:metabolism*; D010084:Oxidation-Reduction; D017680:Potassium Compounds; D013329:Structure-Activity Relationship; D013431:Sulfates
D002412:Cations; D004277:DNA, Single-Stranded; D004279:DNA, Viral; D017895:Manganese Compounds; D008665:Metalloporphyrins; D016376:Oligonucleotides, Antisense; D017680:Potassium Compounds; D013431:Sulfates; C009007:potassium persulfate; D003851:Deoxyribonucleases; D004229:Dithiothreitol