A RATIONAL APPROACH TO ANTI-HIV DRUG DESIGN

我们的根本目标是改进设计抗HIV病毒的方法 与细胞质HIV病毒相互作用最大的药物 核酸(高活性)和与宿主的最小相互作用 通过两种广泛的方法获得细胞染色体DNA(低毒)： 分子靶向--选择性结合HIV来源的药物 细胞质中的核酸由于结构和动态的原因 病毒和宿主核酸之间的差异，以及 将药物与庞大的群体分开，这些群体将相互作用 强烈地与病毒核酸结合，并利用大小依赖关系 将分子分配到原子核中。的基本理念 抗HLV药物的分子靶向如下：(I)通过使用范围 尖端技术，包括先进的核磁共振和分子 图形.建模方法.现有化合物与 可以增强RNA的特定二级结构特征，并 可以设计出与病毒特异相互作用的新化合物 RNA：(Ii)由于宿主细胞的DNA和RNA合成 在细胞核中，艾滋病毒的复制新陈代谢可以 有选择地打乱了。病毒rna具有复杂的二级结构。 (堆叠的单股、发夹双螺旋截面和 碱基不匹配或不匹配的双链区域)。许多人 具有异常次级结构特征的区域代表 病毒RNA转化为病毒的关键控制区 前病毒DNA和非常有吸引力的设计目标 抗艾滋病毒药物。将对所有新的 比较合成化合物对RNA的亲和力 一种标准的染色质制剂。更详细的动力学、核磁共振和 计算机建模研究将在最活跃的 与特定二级结构紧密结合的化合物 核糖核酸的特征，但与染色质结合较弱。基于这些 研究，将在分子的帮助下设计新的化合物 建模方法。这些新化合物应该有显著的 增强了对病毒RNA的亲和力。药学的基本理念 细胞质中的区域化，在那里是重要的代谢 病毒核酸的过程可以被破坏是如此巨大 分子从细胞质进入细胞的速度很慢 可能发生许多有毒过程的核。一系列分子 将设计为具有体积较大的取代基，以保持或 实际上增强了与病毒RNA的结合。的分配系数 所有新化合物都将在合成过程中进行测定和调整 使潜在药物获得良好细胞质的程序 浓度。这些大分子进入原子核的过程 一种标准的细胞系将通过荧光进行监测 用显微镜评估大小和运输之间的关系 进入原子核。

Our fundamental goal is to improve methods of designing anti-HIV drugs which have maximum interactions with cytoplasmic HIV viral nucleic acids (high activity) and minimum interactions with host cell chromosomal DNA (low toxicity) by two broad approaches: molecular targeting - drugs that selectively bind to HIV derived nucleic acids in the cell cytoplasm due to structural and dynamic differences between viral and host nucleic acids, and compartmentalization drugs with bulky groups that will interact strongly with viral nucleic acids and exploit the size dependence of partitioning of molecules into the nucleus. The basic ideas for molecular targeting of anti-HlV drugs follow: (i) by using a range of sophisticated techniques, including advanced NMR and molecular graphics-modeling methods, binding of existing compounds to specific secondary structural features of RNA can be enhanced and new compounds can be designed that specifically interact with viral RNA: (ii) since the DNA and RNA synthesis of the host cell occurs in the nucleus, the replicative metabolism of the HIV virus can be selectively disrupted. Viral RNA has a complex secondary structure (stacked single-strands, hairpin double-helical sections, and duplexed regions with unmatched or mismatched bases). Many of the regions with unusual secondary structural features represent critical control regions for the conversion of viral RNA into the proviral DNA and the very attractive targets for the design of anti-HIV drugs. Binding studies will be conducted for all new synthetic compounds to compare their affinity for RNA relative to a standard chromatin preparation. More detailed kinetics, NMR and computer modeling studies will be conducted on the most active compounds which bind strongly to specific secondary structural features of RNA but which bind weakly to chromatin. Based on these studies, new compounds will be designed with the aid of molecular modeling methods. These new compounds should have significantly enhanced affinity for the viral RNA. The basic idea for drug compartmentalization in the cytoplasm where important metabolic processes of viral nucleic acids can be disrupted is that bulky molecules pass quite slowly from the cell cytoplasm into the cell nucleus where many toxic processes can occur. A range of molecules will be designed with bulky substituents situated to maintain or actually enhance binding to viral RNA. Partition coefficients for all new compounds will be determine and adjusted in synthetic procedures such that the potential drugs achieve good cytoplasmic concentrations. Passage of these bulky molecules into the nucleus of a standard cell line will be monitored by fluorescence microscopy to evaluate the correlation between size and transport into the nucleus.