HIGH AFFINITY AGONISTS OF HIV1 DEPENDENT FUSION

新型HIV-1复制拮抗剂的研究进展 水平，通过阻断gp120/CD4相互作用和/或结构变化， 代表着。由以下组成的合成组合库(SCL) 数千到数百万种杂环化合物、肽类化合物或 多肽将被用来开发这种拮抗剂。SCL的优势 方法依赖于高活性化合物的快速鉴定 从单个化合物的大水池中。第一个目标是筛选10个 分离具有不同化学特性的SCL(即，N- 烷基化肽、二肽类、多胺、吲哚-吡啶-2 咪唑、N-烷基氨基环脲、硫脲和双环 胍类)具有抑制融合活性的能力。 用两种检测系统模拟T-1重组HIV-1糖蛋白 细胞系嗜性(T-嗜性)和巨噬细胞嗜性(M-嗜性)。 将对这些超临界流体进行去卷积，以识别化合物 在两个测定系统中具有拮抗活性或具有特定的 在给定的热带系统中的活动。第二个策略将应用沙田至中层 具有最佳拮抗剂的多肽的鉴定方法 模仿HIV-1中发现的活性和/或构象 糖蛋白。该方法包括：1)选择关键残基 在已知的抗病毒多肽序列中(例如，C4衍生物、两亲性 基于现有和/或提议的传统 SAR研究；2)生成偏向SCL，其中这些关键位置 随机化；以及3)识别那些具有更强抑制作用的类似物 活性相对于原来的多肽支架。必要时， 随后将应用SCL方法进一步优化新的 确定的化合物达到纳摩尔范围内的活性，和/或 以提高其生物稳定性和生物利用度。决赛 一系列的研究旨在评估大脑的活动水平 不同化合物对HIV-1感染性的新鉴定 复制试验中M嗜性和T嗜性的原型分离株。 此外，对其发病机制的研究也是值得关注的。 这些拮抗者的行动将被启动。

The development of novel antagonists of HIV-1 replication at the entry level, via blockade of gp120/CD4 interactions and/or structural changes, represents. Synthetic combinatorial libraries (SCLs) made up of thousands to millions of heterocyclic compounds, peptidomimetics or peptides will be used to develop such antagonists. The strength of SCL approaches relies on the rapid identification of highly active compounds from large pools of individual compounds. A first aim is to screen 10 separate SCLs that have different chemical characteristics (i.e., N- alkylated peptides, dipeptidomimetics, polyamines, indole-pyrido- imadazoles, N-alkyl amino cyclic ureas and thioureas and bicyclic guanidines) for their ability to inhibit fusogenic activity mediated by HIV-1 recombinant glycoprotein using two assay systems mimicking the T- cell line-tropic (T-tropic) and macrophage-tropic (M-tropic). Deconvulation of these SCLs will be carried out to identify compounds having either antagonist activity in the two assay systems or specific activity in a given tropic system. A second strategy will apply the SCL approaches to the identification of peptides having optimized antagonist activities and/or conformations that would mimic those found in HIV-1 glycoproteins. This approach will consist of: 1) selecting key residues in known antiviral peptide sequences (e.g., C4 derivatives, amphipathic alpha-helical attitudes) based on existing and/or proposed traditional SAR studies; 2) generating a biased SCL in which these key positions are randomized; and 3) identifying those analogs having greater inhibitory activity relative to the original peptide scaffold. When necessary, the SCL approach will be subsequently applied to further optimize the newly identified compounds to reach activities in the nanomolar range, and/or to increase their biological stability and bioavailability. The final series of studies are designed to evaluate the level of activity of the newly identified compounds in HIV-1 infectivity using different prototype M-tropic and T-tropic isolates in replication assays. Furthermore, studies toward the understanding of the mechanisms of action of these antagonists will be initiated.