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DESIGN OF NEW OLIGONUCLEOTIDE DERIVATIVES RESISTANT TO CELL NUCLEASES DEGRADATION
M. B. GOTTIKH, M. G. IVANOVSKAYA, E. A. SKRIPKIN, Z. A. SHIABAROVA
A. N. Belozersky Laboratory of Molecular Biology and Bioorganic Chemisry , Moscow State University
Abstract: A new type of modified antisenso oligodeoxyribonucleoticles is suggested, contai-ning an intercalating drug (e. g., daunomycin (Dnm-NH2)) at one end of the oligonucleotide, and a compound, improving the oligonucleotide transport into the cell, e. g., polymyxin B1 (PmH) at its other end. Schemes for joining these antibiotics to the terminal groups of oligonucleotides have been developed. From undecanucleotide pTGTAAAACGACp (I), the corresponding derivative (Pm)pTGTAAAACGACp (NH-Dnm) XII) was obtained with 20% yield. It was found that joining of daunomycin significantly lowers the rate of the oligonucleotide's exonuclease degradation, whereas jojning of polymyxin blocks the degradation completely. Derivative (II) is much more stable to hydrolysis by cell enzymes that the unmodified oligonucleotide (I): upon incubation with E. coli cells (I) is quantitatively hydrolyzed with in 40 minutes while (II) is hyd-rolyzed by 30% with in 24 h. Derivative (II) is also better adsorbed by E. coli cells. This sort of derivative of antisense oligonucleotides may prove to be efficient inhibitors of the gene expression.
Russian Journal of Bioorganic Chemistry 1990, 16 (4):514-523