A linear five-ring pyrrole-imidazole polyamide-triphenylphosphonium conjugate targeting a mitochondrial DNA mutation efficiently induces apoptosis of HeLa cybrid cells carrying the mutation
A linear five-ring pyrrole-imidazole polyamide-triphenylphosphonium conjugate targeting a mitochondrial DNA mutation efficiently induces apoptosis of HeLa cybrid cells carrying the mutation
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DOI：
10.1016/j.bbrc.2021.08.088
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发表时间：
2021-09-03
影响因子：
3.1
通讯作者：
Nagase, Hiroki
中科院分区：
文献类型：
--
作者：
Koshikawa, Nobuko;Kida, Yuki;Nagase, Hiroki
线粒体DNA的体细胞突变可能为癌症治疗提供新的途径，因为它们与许多癌症和同质性倾向有关。考虑到线粒体的特征及其相对较小的基因组大小，基于核苷酸的靶向方法是一个相当有前途的选择。为了探讨短线状N-甲基吡咯-N-甲基咪唑聚酰胺(PI聚酰胺)的有效性，我们合成了一种五环短PI聚酰胺，它与三苯基膦阳离子(TPP)偶联后为A3243G线粒体突变提供序列特异性归位。这种PI聚酰胺-TPP能够在HeLamtA3243G胞体细胞中诱导细胞毒性，同时通过熔融温度分析优先结合含有A3243G基序的寡核苷酸。PI聚酰胺-TPP也定位于HeLamtA3243G细胞的线粒体，并以突变特异性的方式诱导线粒体活性氧的产生、有丝分裂和细胞凋亡；正常人皮肤成纤维细胞也相对不受影响，提示对突变的线粒体具有区分选择性，这为通过短线性PIP-TPP的线粒体归巢治疗癌症提供了新的前景。(C)2021年提交人。由爱思唯尔公司出版。这是一篇基于CC by License(http://creativecommons.org/licenses/by/4.0/).的开放获取文章
Somatic mutations in mitochondrial DNA may provide a new avenue for cancer therapy due to their associations to a number of cancers anda tendency of homoplasmicity. In consideration of mitochondrial features and its relatively small genome size, a nucleotide-based targeting approach is a considerably more promising option. To explore the efficacy of short linear N-methylpyrrole-N-methylimidazole polyamide (PI polyamide), we synthesized a five-ring short PI polyamide that provided sequence-specific homing for the A3243G mitochondrial mutation upon conjugation with triphenylphosphonium cation (TPP). This PI polyamide-TPP was able to induce cytotoxicity in HeLamtA3243G cybrid cells, while pre -serving preferential binding for oligonucleotides containing the A3243G motif from melting temperature assays. The PI polyamide-TPP also localized in the mitochondria in HeLamtA3243G cells and induced mitochondrial reactive oxygen species production, mitophagy and apoptosis in a mutation-specific fashion compared to the wild-type HeLamtHeLa cybrids; normal human dermal fibroblasts were also relatively unaffected to suggest discriminating selectivity for the mutant mitochondria, offering a novel outlook for cancer therapy via mitochondrial homing of short linear PIP-TPPs. (c) 2021 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).