Simultaneous mutations at Tyr‐181 and Tyr‐188 in HIV‐1 reverse transcriptase prevents inhibition of RNA‐dependent DNA polymerase activity by the bisheteroarylpiperazine (BHAP) U‐90152s
- 14 August 1995
- journal article
- research article
- Published by Wiley in FEBS Letters
- Vol. 370 (1-2) , 59-62
- https://doi.org/10.1016/0014-5793(95)00793-9
Abstract
The replacement of either Tyr-181 or Tyr-188 of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) by the corresponding HIV-2 RT amino acids Ile-181 or Leu-188 is known to result in active mutant enzymes (Y181I; Y188L) with virtual loss of sensitivity towards three structural classes of nonnucleoside RT inhibitors; L-697,661, nevirapine, and TIBO R82913. The bisheteroarylpiperazine (BHAP) U-90152S, a highly specific inhibitor (IC50, 0.29 ± 0.01 μM) of HIV-1 RT, inhibited the recombinant Y181I and Y188L HIV-1 RT mutants with IC50 values of 3.6 ± 0.15 μM and 0.71 ± 0.02 μM, respectively. Construction and in vitro analysis of double mutants Y181I/Y188L and Y181C/Y188L of HIV-1 RT showed > 150-fold resistance to U-90152S. An HIV-2 mutant containing amino acids 176–190 from HIV-1 RT acquired full sensitivity to U-90152S (IC50, 0.29 ± 0.01 μM). It is concluded tha simultaneous mutations at Tyr-181 and Tyr-188 of HIV-1 RT promotes resistance to U-90152SKeywords
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