POTENTIAL SYNERGISTIC INHIBITORS OF HIV INFECTIVITY

HIV 感染的潜在协同抑制剂

• 批准号: 3144760
• 负责人: VASU NAIR
• 金额: $ 10.45万
• 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/3144760
• 关键词: 2'3' dideoxynucleoside; AIDS; HIV envelope protein gp120; HIV infections; antiAIDS agent; antiviral agents; cytotoxicity; drug design /synthesis /production; enzyme inhibitors; glycoproteins; glycosylation; human immunodeficiency virus; human immunodeficiency virus 1; human immunodeficiency virus 2; hypoxanthines; inosine; lymphocyte; prodrugs; reverse transcriptase inhibitors; 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.

这种被称为获得性免疫的致命疾病的病原体 缺乏综合症(AIDS)是一种嗜淋巴的逆转录病毒，称为 人类免疫缺陷病毒(HIV-1)。其他与HIV-1相关的逆转录病毒 也在被确认。HIV-1的复制周期提供了一个数字 通过精心设计的治疗性疗法可能进行干预的靶点 探员们。这项研究计划的长期目标是为 新的核苷、碳水化合物和 具有抗艾滋病治疗潜力的相关分子。这个 这项研究调查的具体目标与潜在的 针对两种HIV感染性的协同抑制剂 重要的翻译后糖基化。靶向的新型化合物 作为HIV逆转录酶抑制剂的合成，战略性地包括 官能化的同系物、前药物和2‘，3’-的位置异构体 二脱氧肌苷(DDL)。潜在的(艾滋病毒的)糖基化抑制剂 糖蛋白gp120)是脱氧诺吉霉素的新型氨基糖 一家人。给出了选择目标化合物的理由。 对这些化合物的化学和生物化学研究旨在 提供有关水解性、亲脂性、底物的信息 肌苷一磷酸脱氢酶(IMPDH)的活性和抑制作用， 和脱氧胞苷激酶的磷酸化。二脱氧次黄嘌呤 本项目合成的核苷和1-脱氧诺吉霉素类似物 将在高度纯化的形式下评估它们抑制 HIV-1和HIV-2对人T4淋巴细胞的感染性和细胞病变效应 细胞系。抑制HIV逆转录酶的新信息 抑制病毒抗原表达，抑制gp120 糖基化、细胞毒性和治疗指数是预期的 从生物评估数据中。联合化疗研究 涉及协同抑制艾滋病毒传染性的工作正在计划之中。这部小说 所提出的化合物具有很高的抗病毒作用和 预计这项调查还将有助于填补一些 这一领域的知识差距。