Small molecules that bind the inner core of gp41 and inhibit HIV envelope-mediated fusion
Small molecules that bind the inner core of gp41 and inhibit HIV envelope-mediated fusion
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DOI：
10.1073/pnas.0601036103
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发表时间：
2006-09-19
影响因子：
11.1
通讯作者：
Harrison, Stephen C.
中科院分区：
文献类型：
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作者：
Frey, Gary;Rits-Volloch, Sophia;Harrison, Stephen C.
HIV-1 通过三聚体病毒包膜糖蛋白 gp160 介导的膜融合进入细胞，该糖蛋白通过单一蛋白水解裂解成稳定相关的 gp120 和 gp41。 gp120/gp41 三聚体可被触发发生不可逆的构象变化。使用旨在模拟 gp41 构象变化的基于蛋白质的测定，我们筛选了阻止融合后 gp41 形成的小分子。鉴定出了几种化合物。一组结构相关的分子抑制融合后样组装体的形成，IC50 约为 5 μM。这些化合物还在细胞-细胞融合和病毒感染性测定中抑制包膜介导的膜融合。因此，我们的筛选确定了有效的融合抑制剂。针对来自 HIV-1 原代分离株的一组包膜蛋白进行测试，这些化合物抑制了广泛的进化枝的融合，包括 M 和 T 热带毒株。它们结合在 gp41 三聚体内核上高度保守的疏水口袋中，该区域先前被确定为潜在的抑制剂位点。
HIV-1 enters cells by membrane fusion, mediated by the trimeric viral envelope glycoprotein gp160, which is processed by a single proteolytic cleavage into stably associated gp120 and gp41. The gp120/gp41 trimer can be triggered to undergo an irreversible conformational change. Using a protein-based assay designed to mimic the gp41 conformational change, we screened for small molecules that prevent the formation of postfusion gp41. Several compounds were identified. One set of structurally related molecules inhibited formation of a postfusion-like assembly with an IC50 of approximate to 5 mu M. The compounds also inhibited envelope-mediated membrane fusion in both cell-cell fusion and viral infectivity assays. Thus, our screen identifies effective fusion inhibitors. Tested against a panel of envelope proteins from primary HIV-1 isolates, the compounds inhibited fusion across a broad range of clades, including both M and T tropic strains. They bind in a highly conserved, hydrophobic pocket on the inner core of the gp41 trimer, a region previously identified as a potential inhibitor site.