Fan N, Rank K B, Evans D B, Thomas R C, Tarpley W G, Sharma S K
Upjohn Laboratories, Kalamazoo, MI 49001, USA.
FEBS Lett. 1995 Aug 14;370(1-2):59-62. doi: 10.1016/0014-5793(95)00793-9.
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 microM) of HIV-1 RT, inhibited the recombinant Y181I and Y188L HIV-1 RT mutants with IC50 values of 3.6 +/- 0.15 microM and 0.71 +/- 0.02 microM, 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 RT mutant containing amino acids 176-190 from HIV-1 RT acquired full sensitivity to U-90152S (IC50, 0.26 +/- 0.01 microM). It is concluded that simultaneous mutations at Tyr-181 and Tyr-188 of HIV-1 RT promotes resistance to U-90152S.
已知用相应的HIV-2逆转录酶（RT）氨基酸异亮氨酸-181或亮氨酸-188替代人类免疫缺陷病毒1型（HIV-1）逆转录酶（RT）的酪氨酸-181或酪氨酸-188会产生对三种结构类型的非核苷RT抑制剂（L-697,661、奈韦拉平和TIBO R82913）几乎失去敏感性的活性突变酶（Y181I；Y188L）。双杂芳基哌嗪（BHAP）U-90152S是一种对HIV-1 RT具有高度特异性的抑制剂（IC50，0.29±0.01微摩尔），分别以3.6±0.15微摩尔和0.71±0.02微摩尔的IC值抑制重组Y181I和Y188L HIV-1 RT突变体。HIV-1 RT双突变体Y181I/Y188L和Y181C/Y188L的构建及体外分析显示对U-90152S具有>150倍的抗性。含有来自HIV-1 RT的氨基酸176-190的HIV-2 RT突变体对U-90152S获得了完全敏感性（IC50，0.26±0.01微摩尔）。结论是HIV-1 RT酪氨酸-181和酪氨酸-188同时发生突变会促进对U-90152S的抗性。
