Bardos T J, Schinazi R F, Ling K H, Heider A R
Department of Medicinal Chemistry, State University of New York, Buffalo, Amherst 14260, USA.
Antimicrob Agents Chemother. 1992 Jan;36(1):108-14. doi: 10.1128/AAC.36.1.108.
Introduction of a reactive 5-mercapto group into some of the cytosine and/or uracil bases of various oligo- and polynucleotides by partial thiolation resulted in several potent inhibitors of the replication of human immunodeficiency virus type 1 (HIV-1) in primary human lymphocytes. These compounds exhibited little if any toxicity against uninfected peripheral blood mononuclear cells and showed 15 to 75 times higher antitemplate activity against a p66/p51 HIV-1 recombinant reverse transcriptase (RT) than against the DNA polymerase alpha from human lymphocytes. In contrast, the unthiolated oligo- and polynucleotides are void of antitemplate activity, and their apparent inhibitory effect on HIV-1 closely paralleled their toxicity for the cells. Partially thiolated poly(dC) (MPdC) was the most potent of all the compounds tested against HIV-1 in peripheral blood mononuclear cells (50% effective concentration, 1.8 micrograms/ml or 0.019 microM), while showing low cytotoxicity (greater than 100 micrograms/ml). The corresponding unmodified poly(dC) showed no anti-HIV-1 activity at 50 micrograms/ml but had pronounced cytotoxicity. MPdC was also a potent inhibitor of HIV-1 RT (50% inhibitory concentration, 0.30 micrograms/ml). The inhibitory activities of thiolated homooligo(dCs) against both HIV-1 replication and HIV-1 RT increased with increasing chain length. The heterooligonucleotides included in this study were designed as structural analogs of portions of the natural primer of HIV-1 RT, i.e., tRNA(3Lys). An 18-mer analog of the 3' terminus, complementary (antisense) to the primer-binding site of the HIV-1 genome, was attached to an oligo(dC) tail and 5-thiolated; this increased its activity and decreased its toxicity. This compound will serve as a new lead in the development of more effective antitemplates against HIV-1.
通过部分硫醇化反应，将一个反应性的5-巯基引入各种寡核苷酸和多核苷酸的一些胞嘧啶和/或尿嘧啶碱基中，得到了几种在原代人淋巴细胞中对1型人类免疫缺陷病毒（HIV-1）复制具有强效抑制作用的化合物。这些化合物对未感染的外周血单核细胞几乎没有毒性，并且对p66/p51 HIV-1重组逆转录酶（RT）的抗模板活性比对人淋巴细胞的DNA聚合酶α高15至75倍。相比之下，未硫醇化的寡核苷酸和多核苷酸没有抗模板活性，它们对HIV-1的明显抑制作用与其对细胞的毒性密切相关。部分硫醇化的聚（dC）（MPdC）是所有测试化合物中对外周血单核细胞中的HIV-1最有效的（50%有效浓度为1.8微克/毫升或0.019微摩尔），同时显示出低细胞毒性（大于100微克/毫升）。相应的未修饰聚（dC）在50微克/毫升时没有抗HIV-1活性，但具有明显的细胞毒性。MPdC也是HIV-1 RT的强效抑制剂（50%抑制浓度为0.30微克/毫升）。硫醇化的同聚寡核苷酸（dC）对HIV-1复制和HIV-1 RT的抑制活性随着链长的增加而增强。本研究中包含的异源寡核苷酸被设计为HIV-1 RT天然引物部分的结构类似物，即tRNA(3Lys)。与HIV-1基因组引物结合位点互补（反义）的3'末端18聚体类似物连接到寡聚（dC）尾部并进行5-硫醇化；这增加了其活性并降低了其毒性。该化合物将成为开发更有效的抗HIV-1抗模板药物的新先导。
