INHIBITION OF HIV REPLICATION BY DHEA AND ITS ANALOGS

DHEA 及其类似物抑制 HIV 复制

• 批准号: 3143310
• 负责人: EARL E HENDERSON
• 金额: $ 15.47万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-07-01 至 1992-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3143310
• 关键词: AIDS; HIV infections; antiAIDS agent; antiviral agents; dehydroepiandrosterone; drug design /synthesis /production; enzyme linked immunosorbent assay; gel electrophoresis; glucose 6 phosphate dehydrogenase; hormone analog; human immunodeficiency virus; human subject; human tissue; lectin; leukocyte activation /transformation; lymphocyte; macrophage; monocyte; nucleic acid biosynthesis; nucleic acid hybridization; virus replication; western blottings; zidovudine

Although progress has been made, we still lack a truly efficient chemotherapy against human immunodeficiency virus (HIV) infection and progression towards AIDS. HIV requires T cell activation and blastogenesis for efficient replication in vitro, thus agents which induce T cell activation and blastogenesis enhance HIV replication. There is evidence to suggest that T cell activation is also required for HIV replication in vivo. Consequently we have attempted to develop a strategy to inhibit HIV replication and progression to AIDS based on these observations. Dehydroepiandrosterone (DHEA), a major adrenal secretory product in men and women, is a potent inhibitor of mammalian glucose-6- phosphate dehydrogenase (G6PDH). DHEA has previously been found to suppress Epstein-Barr virus (EBV)-induced morphologic transformation and stimulation of DNA synthesis in human peripheral blood lymphocytes (PBLs) (Henderson et al., Carcinogenesis 2:683, 1981). 16 alpha-Br-epiandrosterone, a DHEA analog, is about 60 times more potent than DHEA as an inhibitor of G6PDH, and is much more effective as an inhibitor of EBV-induced transformation. The ability of ribonucleosides and deoxyribonucleosides to 1 reverse the anti-proliferative and anti-differentiating effects of DHEA strongly suggests that inhibition of nucleic acid synthesis is a primary target for these biological effects of DHEA and DHEA analogs. In preliminary experiments we have found that novel synthetic analogs of DHEA, 16 alpha-fluoro-5-androsten-17-one (8354) and 3 beta-hydroxy-16 alpha-fluoro-5 alpha-androstan-17-one (hydroxy 8356) inhibit HIV replication in PHA-treated PBLs. Inhibition of HIV replication was not due to cell toxicity of these compounds. Since DHEA and its analogs are relatively nontoxic, they represent a novel class of compounds with potential for therapy of HIV-infected individuals. Here we propose 1) to directly test this hypothesis by examining the ability of DHEA and synthetic analogs of DHEA to inhibit HIV replication in control and phytohemagglutin (PHA)-stimulated PBLs and continuously proliferating T cell lines; 2) test the ability of DHEA and synthetic analogs to act synergistically with 3'azido-2',3'- dideoxythymidine (AZT) in inhibiting HIV replication. DHEA or its synthetic analogs has the potential of being an efficient adjunct therapy with conventional antiviral compounds in treating HIV infection.

尽管取得了进展，但我们仍然缺乏真正的高效 对人免疫缺陷病毒（HIV）感染的化学疗法 和向艾滋病的发展。 艾滋病毒需要T细胞激活，并且 囊泡发生以进行有效的体外复制，因此 诱导T细胞激活和爆发增强HIV复制。 有证据表明T细胞激活也是 体内艾滋病毒复制所必需的。 因此我们有 试图制定抑制艾滋病毒复制的策略和 基于这些观察结果向艾滋病发展。 脱氢表雄酮（DHEA），一种主要的肾上腺分泌物 在男性和女人中，是哺乳动物葡萄糖-6-的有效抑制剂 磷酸盐脱氢酶（G6PDH）。 以前已经发现DHEA 抑制爱泼斯坦 - 巴尔病毒（EBV）诱导的形态学 人外周中DNA合成的转化和刺激 血液淋巴细胞（PBL）（Henderson等人，癌变2：683， 1981）。 16 Alpha-br- epiandrostrolone，一个DHEA类似物，约为60 比DHEA作为G6PDH的抑制剂更有效，而且很大 作为EBV诱导转化的抑制剂更有效。 这 核糖核苷和脱氧核糖核苷至1反向的能力 DHEA的抗增殖和抗分化作用 强烈建议抑制核酸合成是一种 DHEA和DHEA的这些生物学作用的主要目标 类似物。 在初步实验中，我们发现了这种新颖 DHEA的合成类似物，16个alpha-fluoro-5-androsten-17- （8354）和3个Beta-Hydroxy-16 Alpha-Fluoro-5 Alpha-Androstan-17- （羟8356）抑制PHA处理的PBL中的HIV复制。 抑制HIV复制不是由于这些细胞的毒性 化合物。 由于DHEA及其类似物相对无毒 它们代表了具有潜力的新型化合物 艾滋病毒感染者的治疗。 在这里我们建议1） 通过检查DHEA和 DHEA的合成类似物抑制对照中的HIV复制和 植物凝集素（PHA）刺激的PBL和不断刺激的PBL 增殖的T细胞系； 2）测试DHEA和 合成类似物与3'Azido-2'，3'-- 二甲氧基林（AZT）抑制HIV复制。 DHEA或ITS 合成类似物具有有效的辅助 常规抗病毒化合物治疗HIV的治疗 感染。