Skip to main page content
U.S. flag

An official website of the United States government

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 1997 Mar;41(3):594-9.
doi: 10.1128/AAC.41.3.594.

Effect of incorporation of cidofovir into DNA by human cytomegalovirus DNA polymerase on DNA elongation

X Xiong  1 , J L Smith, M S Chen
Affiliations

Effect of incorporation of cidofovir into DNA by human cytomegalovirus DNA polymerase on DNA elongation

X Xiong et al. Antimicrob Agents Chemother. 1997 Mar.

Abstract

Cidofovir (CDV) (HPMPC) has potent in vitro and in vivo activity against human cytomegalovirus (HCMV), CDV diphosphate (CDVpp), the putative antiviral metabolite of CDV, is an inhibitor and an alternate substrate of HCMV DNA polymerase. CDV is incorporated with the correct complementation to dGMP in the template, and the incorporated CDV at the primer end is not excised by the 3'-to-5' exonuclease activity of HCMV DNA polymerase. The incorporation of a CDV molecule causes a decrease in the rate of DNA elongation for the addition of the second natural nucleotide from the singly incorporated CDV molecule. The reduction in the rate of DNA (36-mer) synthesis from an 18-mer by one incorporated CDV is 31% that of the control. However, the fidelity of HCMV DNA polymerase is maintained for the addition of the nucleotides following a single incorporated CDV molecule. The rate of DNA synthesis by HCMV DNA polymerase is drastically decreased after the incorporation of two consecutive CDV molecules; the incorporation of a third consecutive CDV molecule is not detectable. Incorporation of two CDV molecules separated by either one or two deoxynucleoside monophosphates (dAMP, dGMP, or dTMP) also drastically decreases the rate of DNA chain elongation by HCMV DNA polymerase. The rate of DNA synthesis decreases by 90% when a template which contains one internally incorporated CDV molecule is used. The inhibition by CDVpp of DNA synthesis by HCMV DNA polymerase and the inability of HCMV DNA polymerase to excise incorporated CDV from DNA may account for the potent and long-lasting anti-CMV activity of CDV.

PubMed Disclaimer

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. J Biol Chem. 1979 Nov 10;254(21):10747-53 - PubMed
    1. Biochem Pharmacol. 1996 Jun 14;51(11):1563-7 - PubMed
    1. J Biol Chem. 1984 Feb 10;259(3):1566-9 - PubMed
    1. Proc Natl Acad Sci U S A. 1985 Apr;82(8):2473-7 - PubMed
    1. J Virol. 1985 Dec;56(3):846-51 - PubMed

LinkOut - more resources