HIGH AFFINITY AGONISTS OF HIV1 DEPENDENT FUSION

新型HIV-1复制抑制剂的研究进展 水平，通过阻断gp 120/CD 4相互作用和/或结构变化， 个代表合成组合文库（SCL）由以下组成： 数千至数百万的杂环化合物、肽模拟物或 肽将用于开发这种拮抗剂。SCL的优势 方法依赖于快速鉴定高活性化合物 从单个化合物的大池中。第一个目标是筛选10 具有不同化学特性的单独SCL（即，不，不 烷基化肽，二肽模拟物，多胺，吲哚-吡啶并- 咪唑、N-烷基氨基环脲和硫脲以及双环 胍类），因为它们能够抑制由 使用两种模拟T- 细胞系嗜性（T-嗜性）和巨噬细胞嗜性（M-嗜性）。 将对这些SCL进行去卷积，以识别化合物 在两种测定系统中具有拮抗剂活性或特异性 在特定的热带系统中的活动。第二项策略将应用SCL 鉴定具有优化的拮抗剂的肽的方法 活性和/或构象将模仿HIV-1中发现的那些 糖蛋白该方法将包括：1）选择关键残基 在已知的抗病毒肽序列（例如，C4衍生物，两亲性 α-螺旋姿态）基于现有的和/或提出的传统的 SAR研究; 2）生成有偏差的SCL，其中这些关键位置是 随机化;和3）鉴定具有更大抑制活性的那些类似物， 相对于原始肽支架的活性。必要时 沙中线方案将于其后应用，以进一步优化 鉴定的化合物达到纳摩尔范围内的活性，和/或 以增加它们的生物稳定性和生物利用度。最终 一系列的研究旨在评估活动的水平， 新发现的化合物在HIV-1感染性使用不同的 复制试验中的原型M-嗜性和T-嗜性分离株。 此外，研究对理解的机制， 将引发这些拮抗剂的作用。

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.