CARRIERS FOR MEMBRANE TRANSPORT OF AIDS-TARGETED DRUGS

在过去的八年里，艾滋病已经导致大约65,000名美国人死亡。 年的特点是免疫系统的严重失衡引起的， 人类免疫缺陷病毒对辅助/诱导T细胞的感染 艾滋病。 这种逆转录病毒通过DNA中间体复制， 与病毒DNA互补的DNA的合成由HIV编码的 聚合酶，逆转录酶，抑制的主要候选人， 艾滋病靶向药物。 2'，3'-双脱氧核苷，如3'-叠氮基-2'，3'- 双脱氧硫脒（AZT）是HIV逆转的有效底物抑制剂 转录酶，它们的掺入导致DNA链终止， 抑制病毒复制。 对于细胞内激活， 双脱氧核苷必须被细胞核苷激酶磷酸化， 产生活性的5’-三磷酸盐。 本申请提出了选择性合成载体的开发 用于将5'-磷酸化的艾滋病药物转运穿过细胞膜。 新的载体结合了立体电子效应的最新进展 和分子形状。 承运人的具体识别要素包括 互补的氢键边缘和疏水位点（芳族基团）， 片或非极性环蕃腔）用于嘌呤或嘧啶碱基， 和阳离子位点结合到磷酸官能团上。 一般合成 所概述的协议预计将允许开发特定的 用于递送广泛的双脱氧核苷-5'- 三磷酸盐穿过细胞膜。 识别的选择性将在NMR滴定中定义， 萃取实验和微量热测量。 运输 单核苷酸-5'-三磷酸和寡核苷酸的效率 通过液体有机膜应该提供一种手段， 新受体的载体性质可以被改进。 所描述的 项目旨在为有效运输提供一个总体解决方案， 这些化合物穿过细胞膜。 这可能会打开新的视角， 艾滋病治疗和扩大候选药物的数量， 对抗这种致命的疾病。

AIDS, which has killed approximately 65,000 Americans over the past eight years is characterized by a severe imbalance of the immune system caused by the infection of helper/inducer T cells by the human immunodeficiency virus HIV. This retrovirus replicates through a DNA intermediate, and the synthesis of DNA complementary to viral DNA is catalyzed by a HIV-encoded polymerase, reverse transcriptase, a prime candidate for inhibition by AIDS-targeted drugs. 2',3'-Dideoxynucleosides like 3'-azido-2',3'- dideoxythimidine (AZT) are efficient substrate inhibitors of HIV reverse transcriptase, and their incorporation leads to DNA chain termination and inhibition of viral replication. For intracellular activation, the dideoxynucleosides must be phosphorylated by cellular nucleoside kinases to yield the active 5'-triphosphates. This application proposes the development of selective synthetic carriers for the transport of 5'-phosphorylated AIDS drugs across cell membranes. The new carriers incorporate recent advances in stereoelectronic effects and molecular shape. Specific recognition elements of the carriers include complementary hydrogen bonding edges and a hydrophobic site (an aromatic sheet or an apolar cyclophane cavity) for the purine or pyrimidine base, and cationic sites to bind to the phosphate functions. General synthetic protocols outlined are expected to allow the development of specific carriers for the delivery of a wide range of dideoxynucleoside-5'- triphosphates across membranes. The selectivity in recognition will be defined in NMR titrations, extraction experiments, and microcalorimetric measurements. The transport efficiencies of mononucleoside-5'-triphosphates and oligonucleotides through liquid organic membranes should provide a means by which the carrier properties of the new receptors could be refined. The described projects intend to provide a general solution to the efficient transport of these compounds across cell membranes. This may open new perspectives in AIDS therapy and widen the number of drug candidates to be considered for fighting this deadly disease.