Polyamine derivatives as selective RNaseA mimics.
Site-selective scission of ribonucleic acids (RNAs) has attracted considerable interest, since RNA is an intermediate in gene expression and the genetic material of many pathogenic viruses. Polyamine-imidazole conjugates for site-selective RNA scission, without free imidazole, were synthesized and tested on yeast phenylalanine transfer RNA. These molecules catalyze RNA hydrolysis non-randomly. Within the polyamine chain, the location of the imidazole residue, the numbers of nitrogen atoms and their relative distances have notable influence on cleavage selectivity. A norspermine derivative reduces the cleavage sites to a unique location, in the anticodon loop of the tRNA, in the absence of complementary sequence. Experimental results are consistent with a cooperative participation of an ammonium group of the polyamine moiety, in addition to it's binding to the negatively charged ribose-phosphate backbone, as proton source, and the imidazole moiety as a base. There is correlation between the location of the magnesium binding sites and the RNA cleavage sites, suggesting that the protonated nitrogens of the polycationic chain compete with some of the magnesium ions for RNA binding. Therefore, the cleavage pattern is specific of the RNA structure. These compounds cleave at physiological pH, representing novel reactive groups for antisense oligonucleotide derivatives or to enhance ribozyme activity.
Fouace
Sandra
S
SESO, UMR 6510 CNRS, Institut de Chimie, Université de Rennes 1, F-35042 Rennes Cedex, France.
Gaudin
Cyril
C
Picard
Sylvie
S
Corvaisier
Sophie
S
Renault
Jacques
J
Carboni
Bertrand
B
Felden
Brice
B
D000926:Anticodon / Q000235:genetics; D001483:Base Sequence; D001665:Binding Sites; D004926:Escherichia coli / Q000235:genetics; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D007093:Imidazoles / Q000378:metabolism; D008274:Magnesium / Q000378:metabolism; D008958:Models, Molecular; D018716:Molecular Mimicry; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009690:Nucleic Acid Conformation; D011073:Polyamines / Q000737:chemistry* / Q000378:metabolism*; D012313:RNA / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D012329:RNA, Bacterial / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D012360:RNA, Transfer, Phe / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D012259:Ribonuclease, Pancreatic / Q000737:chemistry / Q000378:metabolism*; D013096:Spermine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D015003:Yeasts / Q000235:genetics
D000926:Anticodon; D007093:Imidazoles; D011073:Polyamines; D012329:RNA, Bacterial; D012360:RNA, Transfer, Phe; C096222:tmRNA; D013096:Spermine; C017921:norspermine; D012313:RNA; C029899:imidazole; D012259:Ribonuclease, Pancreatic; D008274:Magnesium