Balzarini J, Karlsson A, De Clercq E
Rega Institute for Medical Research, Katholieke Universiteit, Leuven, Belgium.
Mol Pharmacol. 1993 Oct;44(4):694-701.
Of the class of the 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)-thymine (HEPT) derivatives, several congeners were found to inhibit (at 50% effective concentrations ranging from 0.02 to 0.6 microgram/ml) the replication of mutant human immunodeficiency virus type 1 (HIV-1) strains that had been selected for resistance against bis(heteroaryl)piperazine, tetrahydroimidazo[4,5,1-jk] [1,4]benzodiazepin-2(1H)-thiones (TIBO), nevirapine, [2',5'-bis-O-(tert- butyldimethylsilyl)-beta-D-ribofuranosyl]-3'-spiro-5''-(4''-amino- 1'',2'' -oxathiole-2'',2''-dioxide) (TSAO), or pyridinone and showed amino acid substitutions at positions 100, 103, 106, 138, and 181, respectively. When HIV-1 strains were selected for resistance against three different HEPT derivatives [i.e., HEPT and its derivatives 5-ethyl-1-ethoxymethyl-6-benzyluracil(E-EBU) and 5-ethyl-1-ethoxymethyl-6-(3,5-dimethylbenzyl)uracil (EBU-dM)], HEPT selected for the mutation 188-Tyr-->His, E-EBU for 181-Tyr-->Cys, and E-EBU-dM for 106-Val-->Ala, in the reverse transcriptase of the mutant viruses. These virus strains showed markedly decreased sensitivity to HEPT derivatives. Moreover, the HEPT-resistant virus strains also proved cross-resistant to virtually all other HIV-1-specific inhibitors, including TIBO, nevirapine, and TSAO.
在1-[(2-羟基乙氧基)甲基]-6-(苯硫基)-胸腺嘧啶(HEPT)衍生物类别中，发现几种同系物能抑制(50%有效浓度范围为0.02至0.6微克/毫升)已被选来对双(杂芳基)哌嗪、四氢咪唑并[4,5,1-jk][1,4]苯并二氮杂卓-2(1H)-硫酮(TIBO)、奈韦拉平、[2',5'-双-O-(叔丁基二甲基甲硅烷基)-β-D-呋喃核糖基]-3'-螺-5''-(4''-氨基-1'',2''-氧硫杂环戊二烯-2'',2''-二氧化物)(TSAO)或吡啶酮产生抗性的突变型人类免疫缺陷病毒1型(HIV-1)毒株的复制，这些毒株在第100、103、106、138和181位分别出现了氨基酸取代。当HIV-1毒株被选来对三种不同的HEPT衍生物[即HEPT及其衍生物5-乙基-1-乙氧基甲基-6-苄基尿嘧啶(E-EBU)和5-乙基-1-乙氧基甲基-6-(3,5-二甲基苄基)尿嘧啶(EBU-dM)]产生抗性时，HEPT选择了突变病毒逆转录酶中的188-酪氨酸→组氨酸突变，E-EBU选择了181-酪氨酸→半胱氨酸突变，EBU-dM选择了106-缬氨酸→丙氨酸突变。这些病毒毒株对HEPT衍生物的敏感性显著降低。此外，对HEPT耐药的病毒毒株实际上也对几乎所有其他HIV-1特异性抑制剂产生交叉耐药，包括TIBO、奈韦拉平和TSAO。
