Cell-permeable stapled peptides based on HIV-1 integrase inhibitors derived from HIV-1 gene products.
Cell-permeable stapled peptides based on HIV-1 integrase inhibitors derived from HIV-1 gene products.
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DOI：
10.1021/cb400495h
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发表时间：
2013-10-18
影响因子：
4
通讯作者：
Tamamura H
中科院分区：
文献类型：
--
作者：
Nomura W;Aikawa H;Ohashi N;Urano E;Métifiot M;Fujino M;Maddali K;Ozaki T;Nozue A;Narumi T;Hashimoto C;Tanaka T;Pommier Y;Yamamoto N;Komano JA;Murakami T;Tamamura H
HIV-1整合酶（IN）是一种对于宿主细胞稳定感染必不可少的酶，因为它催化病毒DNA插入基因组，因此是抗HIV药物开发的一个有吸引力的靶标。早些时候，我们发现Vpr衍生的肽对HIV-1 IN具有抑制活性。这些 Vpr 衍生肽最初位于亲本 Vpr 蛋白的 α 螺旋区域。在抑制肽中添加八精氨酸基团可显着抑制 HIV 复制，并与细胞通透性增加相关，但也具有相对较高的细胞毒性。在目前的研究中，采用一类新型稳定α-螺旋拟肽——钉合肽来增强上述先导肽的细胞通透性。设计、合成了一系列钉合肽，这些肽具有由钌催化的连续各圈 α 螺旋之间的闭环复分解反应形成的烃键，并评估了其生物活性。在基于细胞的检测中，一些钉合肽显示出与原始含八精氨酸的肽 (2) 相当的有效抗 HIV 活性，但细胞毒性较低。荧光成像实验表明，这些钉合肽具有显着的细胞渗透性，CD 分析显示它们形成 α 螺旋结构，而未钉合的同源物形成 β 折叠结构。将这种装订策略应用于 Vpr 衍生的 IN 抑制肽，导致其在细胞中的效力显着增加，并显着降低其细胞毒性。
HIV-1 integrase (IN) is an enzyme which is indispensable for the stable infection of host cells because it catalyzes the insertion of viral DNA into the genome and thus is an attractive target for the development of anti-HIV agents. Earlier, we found Vpr-derived peptides with inhibitory activity against HIV-1 IN. These Vpr-derived peptides are originally located in an α-helical region of the parent Vpr protein. Addition of an octa-arginyl group to the inhibitory peptides caused significant inhibition against HIV replication associated with an increase in cell permeability but also relatively high cytotoxicity. In the current study, stapled peptides, a new class of stabilized α-helical peptidomimetics were adopted to enhance the cell permeability of the above lead peptides. A series of stapled peptides, which have a hydrocarbon link formed by a ruthenium-catalyzed ring-closing metathesis reaction between successive turns of α-helix, were designed, synthesized, and evaluated for biological activity. In cell-based assays some of the stapled peptides showed potent anti-HIV activity comparable with that of the original octa-arginine-containing peptide (2) but with lower cytotoxicity. Fluorescent imaging experiments revealed that these stapled peptides are significantly cell permeable, and CD analysis showed they form α-helical structures, whereas the unstapled congeners form β-sheet structures. The application of this stapling strategy to Vpr-derived IN inhibitory peptides led to a remarkable increase in their potency in cells and a significant reduction of their cytotoxicity.
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影响因子：
7.3
作者：
Suzuki S;Urano E;Hashimoto C;Tsutsumi H;Nakahara T;Tanaka T;Nakanishi Y;Maddali K;Han Y;Hamatake M;Miyauchi K;Pommier Y;Beutler JA;Sugiura W;Fuji H;Hoshino T;Itotani K;Nomura W;Narumi T;Yamamoto N;Komano JA;Tamamura H
通讯作者：
Tamamura H
影响因子：
3.6
作者：
Semenova, EA;Johnson, AA;Pommier, Y
通讯作者：
Pommier, Y
影响因子：
3.5
作者：
Suzuki, Shintaro;Maddali, Kasthuraiah;Tamamura, Hirokazu
通讯作者：
Tamamura, Hirokazu
影响因子：
15
作者：
Boal, Amie K.;Guryanov, Ivan;O'Leary, Daniel J.
通讯作者：
O'Leary, Daniel J.
影响因子：
4
作者：
Okamoto, Toru;Zobel, Kerry;Czabotar, Peter E.
通讯作者：
Czabotar, Peter E.