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

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 pAAApcX modified by ribo, arabino or xylo 5′-phosphonate unit pcX 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 pcXAAA afforded tetramers with excellent activation efficiency and with complete stability against cleavage by phosphomonoesterases. [Copyright &y& Elsevier]