Open AccessNucleotide Pyrophosphatase/Phosphodiesterase 1 Is Responsible for Degradation of Antisense Phosphorothioate Oligonucleotides
Author(s) -
Marzena Wójcik,
Marcin Cieślak,
Wojciech J. Stec,
James W. Goding,
Maria Koziołkiewicz
Publication year - 2007
Publication title -
oligonucleotides/oligonucleotides.
Language(s) - English
Resource type - Journals
eISSN - 1557-8526
pISSN - 1545-4576
DOI - 10.1089/oli.2007.0021
Subject(s) - exonuclease , oligonucleotide , phosphodiester bond , pyrophosphatase , biology , biochemistry , inorganic pyrophosphatase , nucleotide , phosphodiesterase , microbiology and biotechnology , nuclease , enzyme , pyrophosphatases , dna , rna , gene , pyrophosphate , dna polymerase
The rapid degradation of unmodified phosphodiester oligodeoxynucleotides (PO-oligos) by exo -and endonucleases limits their application as antisense constructs and requires the synthesis and use of modified oligonucleotides. Phosphorothioate analogs of oligonucleotides (PS-oligos) are much more stable against nucleolytic degradation than their unmodified counterparts, and this is one of the reasons for which they are a promising class of antisense oligonucleotides. However, PS-oligos also undergo slow hydrolysis by enzymes present in plasma. The oligonucleotide degradation proceeds mainly from the 3' -end, resulting in the formation of a typical ladder of shorter products and the release of the mononucleoside 5' -phosphorothioates. So far, little has been known concerning the molecular identity of the enzymes involved in the degradation of PS-oligos. We now identify the human plasma 3' -exonuclease responsible for their degradation as a soluble form of nucleotide pyrophosphatase/phosphodiesterase 1 (NPP1) (EC 3.1.4.1/EC 3.6.1.9), also known as the plasma cell differentiation antigen PC-1. We also show that adenosine or deoxyadenosine (alpha-thio)triphosphates can act as potent inhibitors of NPPs.