Somatic mutations in mitochondrial DNA may provide a new avenue for cancer therapy due to their associations to a number of cancers and a 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 preserving 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.

线粒体 DNA 中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相关并且具有同质性的趋势。考虑到线粒体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更有前景的选择。探索短线型N-甲基吡咯-N的功效-甲基咪唑聚酰胺（PI 聚酰胺），我们合成了一种五环短 PI 聚酰胺，在与三苯基鏻阳离子 (TPP) 结合后为 A3243G 线粒体突变提供序列特异性归巢。这种 PI 聚酰胺-TPP 能够在 HeLamtA3243G 杂种细胞中诱导细胞毒性，同时保留与来自熔解温度测定的 A3243G 基序的寡核苷酸的优先结合。与野生型 HeLamtHeLa 胞质杂种相比，PI 聚酰胺-TPP 也位于 HeLamtA3243G 细胞的线粒体中，并以突变特异性方式诱导线粒体活性氧的产生、线粒体自噬和细胞凋亡；正常人皮肤成纤维细胞也相对不受影响，表明对突变线粒体的区分选择性，