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扩展聚阴离子科萨烷药效基团作为提高抗HIV效力的一种策略。

Extension of the polyanionic cosalane pharmacophore as a strategy for increasing anti-HIV potency.

作者信息

Cushman M, Insaf S, Paul G, Ruell J A, De Clercq E, Schols D, Pannecouque C, Witvrouw M, Schaeffer C A, Turpin J A, Williamson K, Rice W G

机构信息

Department of Medicinal Chemistry, School of Pharmacy, Purdue University, West Lafayette, Indiana 47907, USA.

出版信息

J Med Chem. 1999 May 20;42(10):1767-77. doi: 10.1021/jm980727m.

DOI:10.1021/jm980727m

Abstract

The anti-HIV agent cosalane inhibits both the binding of gp120 to CD4 as well as an undefined postattachment event prior to reverse transcription. Several cosalane analogues having an extended polyanionic "pharmacophore" were designed based on a hypothetical model of the binding of cosalane to CD4. The analogues were synthesized, and a number of them displayed anti-HIV activity. One of the new analogues was found to possess enhanced potency as an anti-HIV agent relative to cosalane itself. Although the new analogues inhibited both HIV-1 and HIV-2, they were more potent as inhibitors of HIV-1 than HIV-2. Mechanism of action studies indicated that the most potent of the new analogues inhibited fusion of the viral envelope with the cell membrane at lower concentrations than it inhibited attachment, suggesting inhibition of fusion as the primary mechanism of action.

摘要

抗艾滋病毒药物科萨烷既能抑制gp120与CD4的结合，又能抑制逆转录之前一个未明确的附着后事件。基于科萨烷与CD4结合的假设模型，设计了几种具有延长多阴离子“药效基团”的科萨烷类似物。合成了这些类似物，其中一些表现出抗艾滋病毒活性。发现其中一种新类似物作为抗艾滋病毒药物的效力相对于科萨烷本身有所增强。尽管新类似物对HIV-1和HIV-2均有抑制作用，但它们作为HIV-1抑制剂比作为HIV-2抑制剂更有效。作用机制研究表明，最有效的新类似物在较低浓度下抑制病毒包膜与细胞膜融合的能力比抑制附着的能力更强，这表明抑制融合是主要作用机制。