Mirabamides A-D, depsipeptides from the sponge siliquariaspongia mirabilis that inhibit HIV-1 fusion
Mirabamides A-D, depsipeptides from the sponge siliquariaspongia mirabilis that inhibit HIV-1 fusion
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DOI：
10.1021/np070306k
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发表时间：
2007-11-01
影响因子：
5.1
通讯作者：
Bewley, Carole A.
中科院分区：
文献类型：
--
作者：
Plaza, Alberto;Gustchina, Elena;Bewley, Carole A.
已从海洋海绵 Siliquariaspongia mirabilis 中分离出四种新的环状缩酚肽，称为米拉巴胺 A-D (1-4)，并显示可有效抑制 HIV-1 融合。通过 NMR 和 ESIMS 阐明了它们的结构，并使用先进的 Marfey 方法和 NMR 确定了氨基酸的绝对立体化学。米拉巴胺含有两个新实体，包括 1-3 中的 4-氯高脯氨酸和一种不寻常的糖基化氨基酸、β-甲氧基酪氨酸 4'-O-α-L-吡喃鼠李糖苷（1、2 和 4 中），以及一种罕见的 N 末端脂肪族羟基酸。这些元素被证明对于抗 HIV 结构-活性关系研究有用。米拉巴胺 A 在中和和融合测定中抑制 HIV-1，IC50 值在 40 至 140 nM 之间，米拉巴胺 C 和 D 也是如此（3 和 190 nM 的 IC50 值在 140 nM 至 1.3 μM 之间，4 的 IC50 值在 3.9,mu M 之间），表明这些肽可以在 HIV-1 进入的早期阶段发挥作用。含有糖基化 β-OMe Tyr 单元的缩酚肽的有效活性表明 β-OMe Tyr 本身对于活性并不重要。在纸片扩散测定中，米拉巴胺 A-C 以 1-5 μg/纸片抑制枯草芽孢杆菌和白色念珠菌的生长。
Four new cyclic depsipeptides termed mirabamides A-D (1-4) have been isolated from the marine sponge Siliquariaspongia mirabilis and shown to potently inhibit HIV- 1 fusion. Their structures were elucidated by NMR and ESIMS, and absolute stereochemistry of the amino acids was determined using advanced Marfey's methods and NMR. Mirabamides contain two new entities, including 4-chlorohomoproline in 1-3 and an unusual glycosylated amino acid, beta-methoxytyrosine 4'-O-alpha-L-rhamnopyranoside (in 1, 2, and 4), along with a rare N-terminal aliphatic hydroxy acid. These elements proved to be useful for anti-HIV structure-activity relationship studies. Mirabamide A inhibited HIV-1 in neutralization and fusion assays with IC50 values between 40 and 140 nM, as did mirabamides C and D (IC50 values between 140 nM and 1.3 mu M for 3 and 190 nM and 3.9,mu M for 4), indicating that these peptides can act at the early stages of HIV- I entry. The potent activity of depsipeptides containing the glycosylated beta-OMe Tyr unit demonstrates that beta-OMe Tyr itself is not critical for activity. Mirabamides A-C inhibited the growth of B. subtilis and C. albicans at 1-5 mu g/disk in disk diffusion assays.