Nucleic Acids Research, Vol 26, Issue 3 778-786, Copyright © 1998 by Oxford University Press
LA Alexandrova, AY Skoblov, MV Jasko, LS Victorova and AA Krayevsky
Replacement of alpha-, beta- and gamma-phosphate groups in 2'-
deoxynucleoside 5'-triphosphates (dNTP) with phosphonate groups yields a
new set of dNTP mimics with potential biological and therapeutic
applications. Here, we describe the synthesis of 15 new dNTPs modified at
alpha-, beta- and gamma-phosphates containing, in the case of dUTP,
reporter and ligand groups at the C5 position of uracil. It was shown that
gamma-substituted dNTPs were substrates for AMV reverse transcriptase
despite of the large size of substituent at the gamma- phosphonate. On the
other hand, these compounds were poorly utilized by DNA polymerase alpha.
For dUTP analogues substituted at both gamma- phosphonate and C5 of uracil,
the substrate affinity was 1-2 orders of magnitude lower than for their
counterparts containing substituents either at gamma-phosphonate or C5
position. Meanwhile, C5-substituted beta,
gamma-dibromomethylenediphosphonates demonstrated poor activity or were not
active at all as substrates for AMV reverse transcriptase. Finally,
2'-deoxythymidine 5'-[beta, gamma-
(methylphosphinyl)methylphosphonyl]-alpha-phosphate and its 3'-azido-3'-
deoxy analog were substrates for AMV reverse transcriptase, but the
substrate activity of these analogues was 50-100 times lower as compared
with dTTP. HIV reverse transcriptase utilized these compounds 1 order of
magnitude less efficiently than AMV reverse transcriptase; terminal
deoxynucleotidyl transferase did not recognize them at all.
ARTICLES
2'-Deoxynucleoside 5'-triphosphates modified at alpha-, beta- and gamma- phosphates as substrates for DNA polymerases
Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 32 Vavilov str., Moscow 117984, Russia.
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