Xf. Xiong et al., EFFECT OF INCORPORATION OF CIDOFOVIR INTO DNA BY HUMAN CYTOMEGALOVIRUS DNA-POLYMERASE ON DNA ELONGATION, Antimicrobial agents and chemotherapy, 41(3), 1997, pp. 594-599
Cidofovir (CDV) (HPMPC) has potent in vitro and in vivo activity again
st human cytomegalovirus (HCMV), CDV diphosphate (CDVpp), the putative
antiviral metabolite of CDV, is an inhibitor and an alternate substra
te of HCMV DNA polymerase, CDV is incorporated with the correct comple
mentation to dGMP in the template, and the incorporated CDV at the pri
mer end is not excised by the 3'-to-5' exonuclease activity of HCMV DN
A polymerase. The incorporation of a CDV molecule causes a decrease in
the rate of DNA elongation for the addition of the second natural nuc
leotide from the singly incorporated CDV molecule, The reduction in th
e rate of DNA (36-mer) synthesis from an 18-mer by one incorporated CD
V is 31% that of the control, However, the fidelity of HCMV DNA polyme
rase is maintained for the addition of the nucleotides following a sin
gle incorporated CDV molecule, The rate of DNA synthesis by HCMV DNA p
olymerase is drastically decreased after the incorporation of two cons
ecutive CDV molecules; the incorporation of a third consecutive CDV mo
lecule is not detectable, Incorporation of two CDV molecules separated
by either one or two deoxynucleoside monophosphates (dAMP, dGMP, or d
TMP) also drastically decreases the rate of DNA chain elongation by HC
MV DNA polymerase. The rate of DNA synthesis decreases by 90% when a t
emplate which contains one internally incorporated CDV molecule is use
d, 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 C
DV.