Nucleotide and oligonucleotide derivatives as enzyme and nucleic acid targeted irreversible inhibitors, biochemical aspects

Abstract

Sequence specific modification of nucleic acids with reactive oligonucleotide derivatives, complementary addressed modification, can provide an efficient approach for specific inactivation of certain cellular nucleic acids. In experiments with ascites tumor Krebs II cells and alkylating oligothymidylate derivatives it was found that alkylating oligonucleotide derivatives enter the living cell and modify complementary sequences in cellular nucleic acids with high efficiency. Complementary addressed modification of poly(A) sequences in cellular RNA with oligothymidylate derivatives was investigated in detail. The results of experiments on alkylation of cellular nucleic acids are consistent with complementary addressed modification of poly(A) sequences in cellular DNA. These results are supported by experiments on modification of chromatin DNA in which it was found that chromatin DNA interacts with oliogothymidylate derivatives more readily than the isolated double stranded DNA. It was found that alkylating oligonucleotide derivatives complementary to a sequence in immunoglobulin mRNA of MOPC 21 cells arrest the cellular immunoglobulin synthesis. Alkylating oligonucleotide derivatives complementary to RNAs of fowl plague virus inhibit virus multiplication in cell culture.