Potent Anti-HTV (type 1 and type 2) activity of polyoxometalates: Structure-activity relationship and mechanism of action
Potent Anti-HTV (type 1 and type 2) activity of polyoxometalates: Structure-activity relationship and mechanism of action
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DOI：
10.1021/jm980263s
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发表时间：
2000-03-09
影响因子：
7.3
通讯作者：
Holan, G
中科院分区：
文献类型：
--
作者：
Witvrouw, M;Weigold, H;Holan, G
一系列多金属氧酸盐已被合成并评估其对 MT-4 细胞中 HIV-1(IIIB) 和 HIV-1(ROD) 复制的抑制作用。所有化合物均表现出抗 HIV-1 和 HIV-2 的活性，但杂多钨酸盐的抗病毒效力因其化学结构而有很大差异。单、双重和三重 Keggin 型化合物对 HIV-1(IIIB) 复制的抗病毒活性相当（IC50：0.4-0.5 μg/mL），而 HIV-B(ROD) 似乎随着每种化合物 Keggin 结构数量的增加而变得不那么敏感。单道森结构和双道森结构也观察到相同的趋势。检查了其中一些化合物对 MT-4 细胞中 HIV-1(RF) 和 SIV(MAC(251)) 复制的抑制作用。它们的抗 HTV-1(RF) 和抗 SIV(MAC(251)) 效力分别与 HIV-1(IIIB) 或 HIV-2(ROD) 毒株相当。多金属氧酸盐是一类聚阴离子化合物，可阻断 HIV 包膜糖蛋白 gp120 与 CD4(+) 细胞的结合。这些化合物干扰抗CD4 mAb与CD4受体的OKT4A/Leu3a表位的结合，化合物24在这方面是最活跃的，并抑制抗gp120 mAb与受感染的MT-4细胞的结合。没有一种多金属氧酸盐抑制特定CXCR4 mAb与SUP-T1细胞的结合，这表明它们不与CXCR4（T-tropic HIV毒株的主要共受体）相互作用，因此充当病毒结合抑制剂，而不是融合抑制剂。
A series of polyoxometalates have been synthesized and evaluated for their inhibitory effects on HIV-1(IIIB) and HIV-1(ROD) replication in MT-4 cells. All compounds showed activity against HIV-1 and HIV-2, but the antiviral potency of the heteropolytungstates varied considerably depending on their chemical structure. The antiviral activity of single, double, and triple Keggin-type of compounds against HIV-1(IIIB) replication was comparable (IC50: 0.4-0.5 mu g/mL), whereas HIV-B(ROD) appeared to become less sensitive with the increasing number of Keggin structures per compound. The same trend was observed for single and double Dawson structures. Some of these compounds were examined for their inhibitory effect on the replication of HIV-1(RF) and SIV(MAC(251)) in MT-4 cells. Their anti-HTV-1(RF) and anti-SIV(MAC(251)) potencies were comparable to those for the HIV-1(IIIB) or HIV-2(ROD) strain, respectively. The polyoxometalates represent a class of polyanionic compounds, which block the binding of the envelope glycoprotein gp120 of HIV to CD4(+) cells. The compounds interfered with the binding of anti-CD4 mAb to the OKT4A/Leu3a epitope of the CD4 receptor, compound 24 being the most active in this regard, and inhibited the binding of anti-gp120 mAb to infected MT-4 cells. None of the polyoxometalates inhibited the binding of a specific CXCR4 mAb to SUP-T1 cells, suggesting that they do not interact with CXCR4, the main co-receptor for T-tropic HIV strains, and thus act as virus binding, and not as fusion, inhibitors.