Design of cell-permeable stapled peptides as HIV-1 integrase inhibitors.
Design of cell-permeable stapled peptides as HIV-1 integrase inhibitors.
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DOI：
10.1021/jm4006516
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发表时间：
2013-07-11
影响因子：
7.3
通讯作者：
Neamati N
中科院分区：
文献类型：
--
作者：
Long YQ;Huang SX;Zawahir Z;Xu ZL;Li H;Sanchez TW;Zhi Y;De Houwer S;Christ F;Debyser Z;Neamati N
HIV-1整合酶（IN）催化病毒DNA整合到宿主基因组中，涉及与宿主蛋白质的几种相互作用。我们以前已经鉴定了来自HIV-1 IN二聚体界面沿着α-螺旋区域的肽IN抑制剂。在此，我们表明，这些肽的适当的烃钉合，以稳定其螺旋结构显着提高了细胞的渗透性，从而允许在细胞培养中的HIV-1复制的抑制。此外，稳定的肽抑制IN与细胞辅因子LEDGF/p75的相互作用。使用荧光素标记的类似物在四种不同的细胞系中证实了钉合肽的细胞摄取。鉴于其增强的效力和细胞渗透性，这些钉合肽不仅可以作为新型HIV-1 IN抑制剂的先导化合物，而且还可以作为原型生物化学探针或“纳米针”，用于阐明HIV-1 IN二聚化和宿主辅因子在其天然细胞环境中的相互作用。
HIV-1 integrase (IN) catalyzes the integration of viral DNA into the host genome, involving several interactions with host proteins. We have previously identified peptide IN inhibitors derived from the alpha-helical regions along the dimeric interface of HIV-1 IN. Herein, we show that appropriate hydrocarbon-stapling of these peptides to stabilize their helical structure remarkably improves the cell permeability, thus allowing inhibition of the HIV-1 replication in cell culture. Furthermore, the stabilized peptides inhibit the interaction of IN with the cellular cofactor LEDGF/p75. Cellular uptake of the stapled peptide was confirmed in four different cell lines using a fluorescein-labeled analogue. Given their enhanced potency and cell permeability, these stapled peptides can serve as not only lead compounds of novel HIV-1 IN inhibitors but also prototypical biochemical probes or ‘nanoneedles’ for the elucidation of HIV-1 IN dimerization and host co-factor interactions within their native cellular environment.
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影响因子：
7.8
作者：
Henchey, Laura K.;Jochim, Andrea L.;Arora, Paramjit S.
通讯作者：
Arora, Paramjit S.
影响因子：
4.8
作者：
Cherepanov, P;Maertens, G;Debyser, Z
通讯作者：
Debyser, Z
影响因子：
5.4
作者：
DeVreese, K;KoflerMongold, V;Werner, G
通讯作者：
Werner, G
影响因子：
120.1
作者：
De Clercq, E
通讯作者：
De Clercq, E
DOI：
10.1073/pnas.0506924102
发表时间：
2005-11-29
影响因子：
11.1
作者：
Cherepanov, P;Ambrosio, ALB;Engelman, A
通讯作者：
Engelman, A