de Vreese K, Debyser Z, Vandamme A M, Pauwels R, Desmyter J, de Clercq E, Anné J
Rega Institute for Medical Research, Katholieke Universiteit Leuven, Belgium.
Virology. 1992 Jun;188(2):900-4. doi: 10.1016/0042-6822(92)90550-9.
The reverse transcriptase (RT) of human immunodeficiency virus type 1 (HIV-1) is the target enzyme for the tetrahydro-imidazo[4,5,1-jk][1,4]- benzodiazepin-2(1H)one and thione (TIBO) derivatives, a class of highly potent and selective anti-HIV agents that specifically inhibit HIV-1 but not HIV-2 replication. The amino acid sequence divergence may be held responsible for the differential sensitivity of HIV-1 RT and HIV-2 RT to the TIBO derivatives. Using site-directed mutagenesis, we have introduced several amino acid substitutions in the conserved regions of HIV-1 RT. Where applicable, the amino acids were replaced by the corresponding amino acids present in HIV-2 RT. The amino acid residues Y181 and Y188 appeared to be critical for the anti-HIV-1 RT activity of the TIBO derivatives, since substitution of these residues by the corresponding HIV-2 amino acids I181 and L188 resulted in a virtual loss of TIBO sensitivity without loss of enzymatic activity.
人类免疫缺陷病毒1型（HIV-1）的逆转录酶（RT）是四氢咪唑并[4,5,1-jk][1,4]-苯并二氮杂䓬-2(1H)酮和硫酮（TIBO）衍生物的作用靶点，TIBO衍生物是一类高效且具有选择性的抗HIV药物，能特异性抑制HIV-1复制，但不抑制HIV-2复制。氨基酸序列差异可能是HIV-1 RT和HIV-2 RT对TIBO衍生物敏感性不同的原因。利用定点诱变技术，我们在HIV-1 RT的保守区域引入了多个氨基酸替换。在适用的情况下，将这些氨基酸替换为HIV-2 RT中存在的相应氨基酸。氨基酸残基Y181和Y188似乎对TIBO衍生物的抗HIV-1 RT活性至关重要，因为用相应的HIV-2氨基酸I181和L188替换这些残基会导致TIBO敏感性几乎丧失，但酶活性并未丧失。
