RATIONAL DEVELOPMENT OF NOVEL ANTI-AIDS DRUGS

新型抗艾滋病药物的合理开发

• 批准号: 3146316
• 负责人: SYLVIA LEE-HUANG
• 金额: $ 21.79万
• 依托单位: NEW YORK UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-01-01 至 1994-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3146316
• 关键词: AIDS; antiAIDS agent; drug adverse effect; drug design /synthesis /production; drug interactions; human immunodeficiency virus 1; laboratory mouse; plant proteins; protein sequence; protein structure function

The long term objective is to carry out rational development of novel anti-AIDS drugs with high potency, low toxicity, and broad clinical applicability. We have discovered several new anti-HIV agents from distinct and unrelated plant species. Some of these are proteins, whereas others are organic polycyclic compounds. These agents exhibit dose-dependent inhibition of cell free HIV-1 infection and replications measured by: a) quantitative focal syncytium formation on CEM-ss monolayers, b) viral core protein p24 expression, and c) viral-associated reverse transcriptase activity in HIV infected H9 cells. We wish to study the structure-function relationship of these anti-HIV compounds so as to enable the rational design of safer and more effective analogues of anti-AIDS drugs. Peptide sequences and conformational requirements responsible for the anti-AIDS activities and cytotoxicity would be mapped. This may make possible the design of specific peptide fragments which may be useful as anti-HIV drugs with less immuno-genicity and improved pharmacokinetic properties (gut stability, biologic half-life, etc.) than their parent proteins. These sequences may then be further modified by targeted design to modulate and enhance their bioactive properties. We would also study the molecular mechanisms of the anti-HIV activity of these compounds so as to learn new strategies for the prevention and treatment of AIDS. A combination of biochemical, cellular, histochemical, and molecular methods will be used to conduct these studies. If the basis of the anti-HIV activity of these compounds lies in selective interactive or uptake, these may be of use in engineering the delivery of these and other drugs for patient treatment. If the basis of their action lies in a fundamental biochemical difference between HIV-infected cells and normal cells, this difference may be investigated and exploited in new interventions of AIDS.

长远目标是合理开发小说 高效、低毒、临床广泛的抗艾滋病药物 适用性。 我们发现了几种新的抗 HIV 药物，它们来自不同的领域。 不相关的植物种类。其中一些是蛋白质，而另一些则是 有机多环化合物。这些药物表现出剂量依赖性 通过以下方法测量对无细胞 HIV-1 感染和复制的抑制： a) CEM-ss单层上定量的焦点合胞体形成， b) 病毒核心蛋白p24表达，和 c) HIV感染的H9中病毒相关的逆转录酶活性 细胞。 我们希望研究这些抗HIV药物的结构与功能关系 化合物，以便能够合理设计更安全、更 抗艾滋病药物的有效类似物。 肽序列和 负责抗艾滋病活动的构象要求和 细胞毒性将被绘制出来。 这可能使设计成为可能 特定的肽片段可用作抗 HIV 药物 较低的免疫原性和改善的药代动力学特性（肠道 稳定性、生物半衰期等）优于其母体蛋白质。 这些 然后可以通过靶向设计进一步修改序列以调节 并增强其生物活性。 我们还将研究其抗 HIV 活性的分子机制。 这些化合物，以便学习预防和预防的新策略 治疗艾滋病。 生化、细胞、 组织化学和分子方法将用于进行这些 研究。 如果这些化合物的抗 HIV 活性的基础在于 在选择性交互或吸收中，这些可能在工程中有用 运送这些药物和其他药物用于患者治疗。 如果 它们的作用基础在于根本的生化差异 HIV感染细胞和正常细胞之间的这种差异可能是 艾滋病新干预措施的研究和利用。