Analysis of Interactions of DNA Polymerase beta and Reverse Transcriptases of Human Immunodeficiency and Mouse Leukemia Viruses with dNTP Analogs Containing a Modified Sugar Residue

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N. A. Lebedeva¹, T. A. Seredina², V. N. Silnikov¹, T. V. Abramova¹, A. S. Levina¹, S. N. Khodyreva¹, N. I. Rechkunova¹, and O. I. Lavrik^1*

¹Institute of Chemical Biology and Fundamental Medicine, Siberian Division of the Russian Academy of Sciences, pr. Lavrentieva 8, 630090 Novosibirsk, Russia; fax: (3832) 333-677; E-mail: lavrik@niboch.nsc.ru

²Novosibirsk State University, ul. Pirogova 2, 630090 Novosibirsk, Russia

^* To whom correspondence should be addressed.

Received August 25, 2004; Revision received September 29, 2004

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Substrate properties of various morpholinonucleoside triphosphates in the reaction of DNA elongation catalyzed by DNA polymerase beta, reverse transcriptase of human immunodeficiency virus (HIV-1 RT), and reverse transcriptase of Moloney murine leukemia virus (M-MuLV RT) were compared. Morpholinonucleoside triphosphates were utilized by DNA polymerase beta and HIV-1 reverse transcriptase as substrates, which terminated further synthesis of DNA, but were virtually not utilized by M-MuLV reverse transcriptase. The kinetic parameters of morpholinoderivatives of cytosine (MorC) and uridine (MorU) were determined in the reaction of primer elongation catalyzed by DNA polymerase beta and HIV-1 reverse transcriptase. MorC was a more effective substrate of HIV-1 reverse transcriptase and significantly less effective substrate of DNA polymerase beta than MorU. The possible use of morpholinonucleoside triphosphates as selective inhibitors of HIV-1 reverse transcriptase is discussed.

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KEY WORDS: viral reverse transcriptases, terminating substrates, DNA polymerase beta, selective inhibition of viral DNA polymerases

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