Inhibition of human immunodeficiency virus type 1 reverse transcriptase by the 5'-triphosphate β enantiomers of cytidine analogs

Academic Article


  • (-)-β-L-2',3'-Dideoxycytidine (L-ddC) and (-)-β-L-2',3'-dideoxy-5- fluorocytidine (L-FddC) have been reported to be potent and selective inhibitors of human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2) in vitro. In the present study, the 5'-triphosphates of L-ddC (L-ddCTP) and L-FddC (L-FddCTP) were demonstrated to competitively inhibit HIV-1 reverse transcriptase (RT), with inhibition constants (K(i)s) of 2 and 1.6 μM, respectively, when a poly(rI)·oligo(dC)10-15 template primer was used; in comparison K(i) values for β-D-2',3'-dideoxycytidine 5'-triphosphate (D- ddCTP) and β-D-2',3'-dideoxy-5-fluorocytidine 5'-triphosphate (D-FddCTP) were 1.1 and 1.4 μM, respectively. Use of the mutant RT at position 184 (substitution of methionine to valine [M184V]), which is associated with resistance to β-L-2',3'-dideoxy-3'-thiacytidine (3TC) and β-L-2',3'- dideoxy-5-fluoro-3'-thiacytidine (FTC), resulted in significant increases (50- to 60-fold) in K(i) values for L-ddCTP and L-FddCTP, whereas the elevation in K(i) values for D-ddCTP and D-FddCTP was moderate (2-fold). L- ddCTP and L-FddCTP did not inhibit human DNA polymerases α and β up to 100 μM. In contrast, D-ddCTP and D-FddCTP inhibited human DNA polymerase β, with K(i) values of 0.5 and 2.5 μM, respectively. By using sequencing analysis, L-ddCTP and L-FddCTP exhibited DNA chain-terminating activities toward the parental HIV-1 RT, whereas they were not a substrate for the mutant M184V HIV-1 RT. L-ddC and L-FddC did not inhibit the mitochondrial DNA content of human cells up to a concentration of 10 μM, whereas D-ddC and D- FddC decreased the mitochondrial DNA content by 90% at concentrations of 1 and 10 μM, respectively. All of these results suggest that further development of L-ddC, and L-FddC in particular, is warranted as a possible anti-HIV candidate.
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    Author List

  • Faraj A; Agrofoglio LA; Wakefield JK; McPherson S; Morrow CD; Gosselin G; Mathe C; Imbach JL; Schinazi RF; Sommadossi JP
  • Start Page

  • 2300
  • End Page

  • 2305
  • Volume

  • 38
  • Issue

  • 10