Activation of human RNase L by 2'- and 5'-O-methylphosphonate-modified oligoadenylates

Bioorg Med Chem Lett. 2012 Jan 1;22(1):181-5. doi: 10.1016/j.bmcl.2011.11.040. Epub 2011 Nov 23.

Abstract

To determine the influence of internucleotide linkage and sugar ring conformation, and the role of 5'-terminal phosphate, on the activation of human RNase L, a series of 2'- and 5'-O-methylphosphonate-modified tetramers were synthesized from appropriate monomeric units and evaluated for their ability to activate human RNase L. Tetramers pAAAp(c)X modified by ribo, arabino or xylo 5'-phosphonate unit p(c)X activated RNase L with efficiency comparable to that of natural activator. Moreover, incorporation of phosphonate linkages ensured the stability against cleavage by nucleases. The substitution of 5'-terminal phosphate for 5'-terminal phosphonate in tetramer p(c)XAAA afforded tetramers with excellent activation efficiency and with complete stability against cleavage by phosphomonoesterases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenine Nucleotides / chemistry*
  • Animals
  • Cell-Free System
  • Chemistry, Pharmaceutical / methods
  • Dimerization
  • Drug Design
  • Endoribonucleases / chemistry*
  • Fluorescence Resonance Energy Transfer / methods
  • Humans
  • Mice
  • Models, Chemical
  • Oligoribonucleotides / chemistry*
  • Organophosphonates / chemistry*
  • Time Factors

Substances

  • Adenine Nucleotides
  • Oligoribonucleotides
  • Organophosphonates
  • 2',5'-oligoadenylate
  • Endoribonucleases
  • 2-5A-dependent ribonuclease