PLANT ANTI-HIV AGENTS

描述：(改编自《调查人员摘要》)这些调查人员 继续进行药用植物提取物的长期筛选和 随后对已发现的引线进行结构修改。的目标是 拟议的研究是从植物提取的物质中发现新的抗艾滋病毒化合物 天然产物及其类似物。具体地说，他们计划隔离和 从之前的71种提取物中识别出有效的抗艾滋病毒成分 利用生物测定定向分离和结构分析未探索的植物物种 特色化。最初，艾滋病毒复制的抑制程度是通过使用 体外H9淋巴细胞P24抗原捕获试验。的结构 将使用现代光谱和x射线来确定单独的抗艾滋病毒的原理 分析。将为Structure选择有前途的、新的活跃线索 新活性引线上类似物的修饰和合成 构效关系及改善其药理作用 配置文件。将使用生化和细胞来研究其作用机制 基于培养的化验。这些线索应该提供新的、有效的、毒性较小的 可能绕过耐药性的候选药物针对不同的阶段 在病毒的生命周期中，表现出最低的毒性，并具有较低的制造成本 成本。两种化合物，4-甲基DCK和DSB，对 进一步发展，与批准的相比，基于新的行动机制 艾滋病毒药物；对主要HIV-1分离株的体外高效力；体外高 治疗指数；以及合成的简易性。该化合物的体内研究 特性(PK、生物利用度和毒性)仍在继续，机理也是如此 行动研究的一部分。计划进行的其他研究包括体外分析 候选药物与已批准药物联合使用时的协同或拮抗作用 艾滋病药物。对艾滋病毒耐药性发展速度的体外研究也将 被执行。申请人希望这两项中至少有一项在结构上 不同的化合物或其类似物应表现出适当的性质 推进临床前毒理学测试和扩大规模 在2000年期间进行生产，目标是在2001年前提交一份IND。

DESCRIPTION: (Adapted from Investigator's Abstract) These investigators are continually pursuing their long-term screening of medicinal plant extracts and subsequent structural modification of discovered leads. The goal of the proposed research is to discover novel anti-HIV compounds from plant-derived natural products and their analogs. Specifically, they plan to isolate and identify the potent anti-HIV principles from extracts of 71 previously unexplored plant species using bioassay-directed isolation and structural chacterization. Initially, inhibition of HIV replication is measured using an in vitro P24 antigen capture assay in H9 lymphocytes. The structures of isolated anti-HIV principles will be determined using modern spectral and x-ray analyses. Promising, new active leads will be selected for structural modification and synthesis of analogs on new active leads in order to determine structure-activity relationships as well as to improve their pharmacological profiles. Mechanisms of action will be investigated using biochemical and cell culture-based assays. These leads should provide new, effective, and less toxic drug candidates, which may circumvent drug resistance, target different stages in the viral life cycle, exhibit minimal toxicity, and have lower manufacturing costs. Two compounds, 4-methy DCK and DSB, have attractive properties for further development, based on novel mechanisms of action compared to approved HIV drugs; high in vitro potency against primary HIV-1 isolates; high in vitro therapeutic indices; and ease of synthesis. Studies of the compound's in vivo properties (pK, bioavailability and toxicity) are continuing, as are mechanism of action studies. Additional studies planned include in vitro analyses of the drug candidates' synergy or antagonism when used in combination with approved HIV drugs. In vitro studies of the rate of HIV resistance development will also be performed. The applicant hopes that at least one of these two structurally diverse compounds, or one of their analogs, should exhibit suitable properties for moving forward into preclinical toxicology testing and scale-up manufacturing during 2000, with the goal of submitting an IND by 2001.