POTENTIAL SYNERGISTIC INHIBITORS OF HIV INFECTIVITY

HIV 感染的潜在协同抑制剂

• 批准号: 3144758
• 负责人: VASU NAIR
• 金额: $ 11.52万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-03-01 至 1993-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3144758
• 关键词: AIDS; HIV infections; RNA directed DNA polymerase; antiviral agents; chemical synthesis; cytotoxicity; enzyme inhibitors; glycoproteins; glycosylation; human immunodeficiency virus; human immunodeficiency virus 1; human immunodeficiency virus 2; hypoxanthines; lymphocyte; tissue /cell culture; virus antigen

The causative agent of the fatal disease known as acquired immune deficiency syndrome (AIDS) is a lymphotropic retrovirus referred to as human immunodeficiency virus (HIV-1). Other retroviruses related to HIV-1 are also being identified. The replicative cycle of HIV-1 offers a number of targets for possible intervention by judiciously designed therapeutic agents. The long-term goals of this research program are to contribute to the chemistry and biochemistry of novel nucleosides, carbohydrates, and related molecules with useful therapeutic potential against AIDS. The specific aims of this research investigation are concerned with potential synergistic inhibitors of HIV infectivity that are directed at two important post-translational glycosylation. The novel compounds targeted for synthesis as HIV reverse transcriptase inhibitors include strategically functionalized congeners, pro-drugs, and positional isomers of 2',3'- dideoxyinosine (ddl). Potential glycosylation inhibitors (of HIV glycoprotein gp120) proposed are novel aminosugars of the deoxynojirimycin family. Justification for the choice of the target compounds is presented. Chemical and biochemical studies on these compounds have been designed to provide information on hydrolytic stabilities, lipophilicities, substrate activities and inhibition of inosine monophosphate dehydrogenase (IMPDH), and phosphorylation by deoxycytidine kinase. The dideoxyhypoxanthine nucleosides and 1-deoxynojirimycin analogues synthesized in this project will be evaluate in highly purified form for their ability to inhibit the infectivity and cytopathic effect of HIV-1 and HIV-2 in human T4-lymphocyte cell lines. New information on inhibition of HIV reverse transcriptase, on inhibition of viral antigen expression, on inhibition of gp120 glycosylation, on cytotoxicity, and on therapeutic indexes are expected from the biological evaluation data. Combination chemotherapeutic studies involving synergistic inhibition of HIV infectivity are planned. The novel compounds proposed have high probability of being antivirally useful and the investigation is also expected to contribute to filling some of the gaps of knowledge in this area.

获得性免疫致命疾病的病原体 艾滋病是一种嗜淋巴细胞逆转录病毒， 人类免疫缺陷病毒（HIV-1）。 与HIV-1相关的其他逆转录病毒 也正在被识别。 HIV-1的复制周期提供了一些 通过合理设计的治疗方法， 剂. 这项研究计划的长期目标是促进 新型核苷、碳水化合物和 相关的分子，对艾滋病有治疗潜力。 的 这项研究的具体目标是关注潜在的 针对两种HIV感染性的协同抑制剂， 重要的翻译后糖基化。 目标化合物 作为HIV逆转录酶抑制剂的合成策略包括 功能化的同系物，前药，和位置异构体的2 '，3'- 双脱氧肌苷（DDL）。 潜在的糖基化抑制剂（HIV 糖蛋白gp 120）是脱氧野尻霉素的新氨基糖 家人 给出了目标化合物的选择依据。 对这些化合物的化学和生物化学研究旨在 提供水解稳定性、亲脂性、底物 肌苷一磷酸脱氢酶（IMPDH）的活性和抑制， 和通过脱氧胞苷激酶的磷酸化。 双脱氧次黄嘌呤 本项目合成的核苷和1-脱氧野尻霉素类似物 将以高度纯化的形式评价它们抑制 HIV-1和HIV-2对人T_4淋巴细胞感染性和细胞病变效应 细胞系 关于抑制HIV逆转录酶的新信息， 抑制病毒抗原表达，抑制gp 120 预计糖基化、细胞毒性和治疗指数 生物学评价数据。 联合化疗研究 包括协同抑制HIV感染性。 小说 所提出的化合物具有很高的抗病毒用途的可能性， 预计调查还将有助于填补一些 这方面的知识空白。