Kinetics of inhibition of HIV type 1 reverse transcriptase-bearing NRTI-associated mutations by apricitabine triphosphate

Antivir Chem Chemother. 2007;18(2):93-101. doi: 10.1177/095632020701800205.


We wished to investigate the effects of various mutations in HIV-1 reverse transcriptase (RT) on biochemical inhibition by the active form of a novel nucleoside termed apricitabine. Accordingly, we studied the efficiency of chain-termination mediated by apricitabine triphosphate (TP) in cell-free assays that used either recombinant wild-type or mutated RTs. We also performed steady-state-kinetics and primer-unblocking assays. Subtype C RTs were also analysed. The results showed that the K65R mutation in RT caused reductions in the efficiency of chain-termination of apricitabine-TP by increasing its Ki. However, K65R did not affect rates of primer unblocking for apricitabine-TP. No significant differences were found between subtype C and subtype B RTs with regard to any of the parameters studied. Other mutations such as M184V, L74V and K103N had no effect on the efficiency of chain termination by apricitabine-TP. Thus, the mechanism of reduced susceptibility to apricitabine of viruses containing K65R in RT seems to be mediated exclusively through a reduction in binding or incorporation of apricitabine-TP. Unlike some other nucleoside analogues, increased excision of incorporated apricitabine does not seem to be a cause of resistance to apricitabine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Deoxycytidine / analogs & derivatives*
  • Deoxycytidine / pharmacology
  • HIV Reverse Transcriptase / antagonists & inhibitors
  • HIV Reverse Transcriptase / chemistry
  • HIV Reverse Transcriptase / genetics*
  • Kinetics
  • Molecular Sequence Data
  • Mutation*
  • Reverse Transcriptase Inhibitors / pharmacology*


  • Reverse Transcriptase Inhibitors
  • Deoxycytidine
  • HIV Reverse Transcriptase
  • apricitabine