PLANT ANTI-HIV AGENTS

描述：（改编自研究者摘要）这些研究者是 持续进行药用植物提取物的长期筛选， 随后对发现的线索进行结构修改。的目标 拟议的研究是从植物中发现新的抗艾滋病毒化合物， 天然产物及其类似物。具体来说，他们计划隔离和 从71种以前的提取物中鉴定出有效的抗艾滋病毒成分 未开发的植物物种使用生物测定定向分离和结构 特征化最初，HIV复制的抑制是使用 H9淋巴细胞中体外P24抗原捕获测定。的结构 分离的抗艾滋病毒的原则将确定使用现代光谱和X射线 分析。有前途的，新的积极领导将被选择为结构 在新的活性先导物上修饰和合成类似物， 结构-活性关系以及改善其药理学 数据区.将使用生物化学和细胞化学方法研究作用机制。 基于培养的测定。这些线索应该提供新的、有效的、毒性较小的 可能避免耐药性的候选药物针对不同的阶段 在病毒生命周期中，表现出最小的毒性， 成本两种化合物，4-甲基DCK和DSB，具有吸引人的性质， 与已批准的相比，基于新的作用机制的进一步开发 HIV药物;对主要HIV-1分离株的高体外效力;高体外 治疗指数;和易于合成。化合物的体内研究 性质（pK，生物利用度和毒性）是持续的，因为是机制 行动研究。计划进行的其他研究包括体外分析 候选药物与已批准的药物联合使用时的协同作用或拮抗作用 艾滋病毒药物。对艾滋病毒耐药性发展速度的体外研究也将 被执行。申请人希望这两个结构中至少有一个 不同的化合物或它们的类似物之一应该表现出合适的性质 用于推进临床前毒理学测试和规模扩大 在2000年期间制造，目标是在2001年之前提交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.