Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, 245N 15th Street, New College Building, Room No, 11102, Philadelphia, PA 19102, USA.
Retrovirology. 2013 Dec 13;10:153. doi: 10.1186/1742-4690-10-153.
We examined the underlying mechanism of action of the peptide triazole thiol, KR13 that has been shown previously to specifically bind gp120, block cell receptor site interactions and potently inhibit HIV-1 infectivity.
KR13, the sulfhydryl blocked KR13b and its parent non-sulfhydryl peptide triazole, HNG156, induced gp120 shedding but only KR13 induced p24 capsid protein release. The resulting virion post virolysis had an altered morphology, contained no gp120, but retained gp41 that bound to neutralizing gp41 antibodies. Remarkably, HIV-1 p24 release by KR13 was inhibited by enfuvirtide, which blocks formation of the gp41 6-helix bundle during membrane fusion, while no inhibition of p24 release occurred for enfuvirtide-resistant virus. KR13 thus appears to induce structural changes in gp41 normally associated with membrane fusion and cell entry. The HIV-1 p24 release induced by KR13 was observed in several clades of HIV-1 as well as in fully infectious HIV-1 virions.
The antiviral activity of KR13 and its ability to inactivate virions prior to target cell engagement suggest that peptide triazole thiols could be highly effective in inhibiting HIV transmission across mucosal barriers and provide a novel probe to understand biochemical signals within envelope that are involved in membrane fusion.
我们研究了先前显示可特异性结合 gp120、阻断细胞受体相互作用并有效抑制 HIV-1 感染性的肽三唑硫醇 KR13 的作用机制。
KR13、硫醇封闭的 KR13b 及其母体非硫醇肽三唑 HNG156 诱导 gp120 脱落，但只有 KR13 诱导 p24 衣壳蛋白释放。由此产生的病毒裂解后病毒形态发生改变，不含 gp120，但保留与中和 gp41 抗体结合的 gp41。值得注意的是，KR13 诱导的 HIV-1 p24 释放被 enfuvirtide 抑制，enfuvirtide 可阻断膜融合过程中 gp41 6 螺旋束的形成，而 enfuvirtide 耐药病毒的 p24 释放则不受抑制。因此，KR13 似乎诱导 gp41 发生与膜融合和细胞进入正常相关的结构变化。KR13 诱导的 HIV-1 p24 释放在几种 HIV-1 谱系以及完全感染性 HIV-1 病毒中均可见。
KR13 的抗病毒活性及其在与靶细胞结合之前失活病毒的能力表明，肽三唑硫醇可能非常有效地抑制粘膜屏障中的 HIV 传播，并提供一种新的探针来了解包膜内参与膜融合的生化信号。
