Learning from host-defense peptides: cationic, amphipathic peptoids with potent anticancer activity.
Learning from host-defense peptides: cationic, amphipathic peptoids with potent anticancer activity.
复制标题
DOI：
10.1371/journal.pone.0090397
复制
发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Barron AE
中科院分区：
文献类型：
--
作者：
Huang W;Seo J;Willingham SB;Czyzewski AM;Gonzalgo ML;Weissman IL;Barron AE
阳离子两亲性宿主防御肽代表了一组有前途的抗癌药物。聚-N-取代的甘氨酸或类肽是一类生物稳定的肽模拟物支架，其可以通过容易的固相合成以高度可调的序列显示多种多样的侧链。在此，我们提出了一个库的抗增殖类肽，模仿的阳离子，两亲性的结构特征的主机防御肽，并探讨这些类肽的结构，抗癌活性和选择性之间的关系。发现几种类肽在低微摩尔浓度下对广泛的癌细胞系有效，包括具有多药耐药性（MDR）的癌细胞，以浓度依赖性方式引起细胞毒性。它们可以渗透到细胞中，但它们的细胞毒性主要涉及质膜扰动。此外，合成的最有效的类肽1在人乳腺癌异种移植模型中显著抑制肿瘤生长，而在小鼠中没有任何明显的急性不良反应。总之，我们的工作提供了重要的结构信息，设计宿主防御肽或其模拟物的抗癌应用。几种阳离子两亲性类肽由于其高溶解度、对蛋白酶降解的稳定性、对癌细胞的广泛、有效的细胞毒性以及克服多药耐药性的能力而非常有吸引力，用于进一步开发。
Cationic, amphipathic host defense peptides represent a promising group of agents to be developed for anticancer applications. Poly-N-substituted glycines, or peptoids, are a class of biostable, peptidomimetic scaffold that can display a great diversity of side chains in highly tunable sequences via facile solid-phase synthesis. Herein, we present a library of anti-proliferative peptoids that mimics the cationic, amphipathic structural feature of the host defense peptides and explore the relationships between the structure, anticancer activity and selectivity of these peptoids. Several peptoids are found to be potent against a broad range of cancer cell lines at low-micromolar concentrations including cancer cells with multidrug resistance (MDR), causing cytotoxicity in a concentration-dependent manner. They can penetrate into cells, but their cytotoxicity primarily involves plasma membrane perturbations. Furthermore, peptoid 1, the most potent peptoid synthesized, significantly inhibited tumor growth in a human breast cancer xenotransplantation model without any noticeable acute adverse effects in mice. Taken together, our work provided important structural information for designing host defense peptides or their mimics for anticancer applications. Several cationic, amphipathic peptoids are very attractive for further development due to their high solubility, stability against protease degradation, their broad, potent cytotoxicity against cancer cells and their ability to overcome multidrug resistance.
登录
查看更多内容
影响因子：
4.8
作者：
Papo, N;Shahar, M;Shai, Y
通讯作者：
Shai, Y
DOI：
10.1073/pnas.0504274102
发表时间：
2005-09-06
影响因子：
11.1
作者：
Dharap, SS;Wang, Y;Minko, T
通讯作者：
Minko, T
影响因子：
8
作者：
Papo, N;Shai, Y
通讯作者：
Shai, Y
影响因子：
11.2
作者：
Papo, N;Braunstein, A;Shai, Y
通讯作者：
Shai, Y
DOI：
10.1165/rcmb.2009-0250oc
发表时间：
2010-12
影响因子：
6.4
作者：
Barlow PG;Beaumont PE;Cosseau C;Mackellar A;Wilkinson TS;Hancock RE;Haslett C;Govan JR;Simpson AJ;Davidson DJ
通讯作者：
Davidson DJ