DEVELOPMENT OF NOVEL ANTI -HIV AGENTS BASED ON HIGHLY' SELECTIVE CHEMOKINE RECEPTOR CXCR$ ANTAGONISTS

我们已经开发了两种类型的抗hiv药物，它们针对的是参与hiv细胞融合的动态超分子机制：一种是共受体（CXCR4）拮抗剂，如T140类似物。另一种是基于C34 （gp41衍生的34-mer肽片段）的融合抑制剂，如SC34。(1)发现一种抗HIV肽T140通过特异性结合趋化因子受体CXCR4抑制X4-HIV-1 （T细胞系嗜性HIV）的进入，CXCR4是X4-HIV进入的共受体。a)采用环状五肽文库将T140必需残基的侧链就近处理。这个集中的文库导致了强效环状五肽的发现。b)在T140的n端区发现了一个新的药效团。基于对t140衍生的药效团的增强，设计并合成了其他低分子量的CXCR4拮抗剂。b)在T140的n端区发现了一个新的药效团。基于对t140衍生的药效团的增强，设计并合成了其他低分子量的CXCR4拮抗剂。2)基于C34的从头设计导致了合成肽SC34的开发，SC34作为gp41靶向hiv细胞融合抑制剂的潜在候选具有以下几个优点（高溶解度，增强抗hiv活性，对T20 [Fuzeon]抗性菌株有效）。这些结果被认为对基于结构的抗hiv药物设计有用。

We have developed two types of anti-HIV agents, which target dynamic supra-molecular mechanism involved in HIV-cell fusion: One is co-receptor (CXCR4) antagonists, such as T140 analogs. The other is fusion inhibitors based on C34, a gp41-derived 34-mer peptide fragment, such as SC34.(1)An anti-HIV peptide, T140, was found to inhibit the entry of X4-HIV-1 (T cell line-tropic HIV) through its specific binding to a chemokine receptor, CXCR4, which is functioned as the co-receptor for the X4-HIV entry.a) A cyclic pentapeptide library was adopted to dispose the side-chains of the indispensable T140 residues in proximity. This focused library led to discovery' of potent cyclic pentapeptides.b) A novel pharmacophore was found in the N-terminal region of T140. Based on the enhancement of T140-derived pharmacophores other low molecular weight CXCR4 antagonists were designed and synthesized.b) A novel pharmacophore was found in the N-terminal region of T140. Based on the enhancement of T140-derived pharmacophores other low molecular weight CXCR4 antagonists were designed and synthesized.2) De novo design based on C34 led to development of a synthetic peptide, SC34, which has several advantages as a potential candidate for gp41-target HIV-cell fusion inhibitors (high solubility, enhanced anti-HIV activity, effectiveness against a T20 [Fuzeon]-resistant strain).These results are thoughtt to be useful for the structure-based drug design of anti-HIV agents.