Biochemical and biological effects of nonionic nucleic acid methylphosphonates

Citations Over TimeTop 15% of 1981 papers

Abstract

Oligodeoxyribonucleoside methylphosphonates with base sequences complementary to the anticodon loop of tRNALys and to the -ACCA-OH amino acid accepting stem of tRNA were prepared by chemical synthesis. Oligodeoxyadenosine methylphosphonates form stable, triple-stranded complexes with both poly(U) and poly(dT). These analogues selectively inhibit cell-free aminoacylation of tRNALys (E. coli) but have no effect on aminoacylation of tRNALys (rabbit). The extent of inhibition is temperature dependent and parallels the ability of the oligomer to bind to poly(U), which suggests that inhibition occurs as a result of oligomer binding to the -UUUU- anticodon loop of tRNALys (E. coli). The failure of the oligodeoxyadenosine methylphosphonates to inhibit tRNALys (rabbit) amino-acylation suggests that there may be a difference between the structure of tRNALys or its interaction with aminoacyl synthetase in the Escherichia coli and rabbit systems. The oligodeoxyadenosine analogues also effectively inhibit polyphenylalanine synthesis in cell-free translation systems derived from both E. coli and rabbit reticulocytes. The extent of inhibition parallels the Tm values of the oligo(A) phosphonate-poly(U) complexes and suggests that the inhibition is a consequence of complex formation with the poly(U) message. Tritium-labeled oligodeoxyribonucleoside methylphosphonates with a chain length of up to nine nucleotidyl units are taken up intact by mammalian cells in culture. All the oligomer analogues tested inhibited, to various extents, colony formation by bacterial, hamster, and human tumor cells in culture.

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