Targeted elimination of mutated mitochondrial DNA by a multi-functional conjugate capable of sequence-specific adenine alkylation
Targeted elimination of mutated mitochondrial DNA by a multi-functional conjugate capable of sequence-specific adenine alkylation
复制标题
通过能够进行序列特异性腺嘌呤烷基化的多功能缀合物，靶向消除突变的线粒体 DNA
DOI：
10.1016/j.chembiol.2021.08.003
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发表时间：
2022
影响因子：
8.6
通讯作者：
Sugiyama Hiroshi
中科院分区：
文献类型：
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作者：
Hidaka Takuya;Hashiya Kaori;Bando Toshikazu;Pandian Ganesh N.;Sugiyama Hiroshi
线粒体DNA（mtDNA）突变导致线粒体疾病，其特征在于线粒体功能异常。虽然消除突变的mtDNA有可能治愈线粒体疾病，但临床试验中没有化学药物能够选择性调节mtDNA突变。在这里，我们构建了一类化合物，包括吡咯-咪唑聚酰胺（PIP），穿膜肽，苯丁酸氮芥，腺嘌呤特异性DNA烷基化试剂。PIPs的序列选择性DNA结合使苯丁酸氮芥能更有效地烷基化突变的腺嘌呤，体外DNA烷基化实验表明，我们的化合物8950 A-Chb（Cl/OH）靶向HeLa S3细胞中的非致病性点突变（m.8950G>A）能特异性烷基化突变的腺嘌呤。此外，该化合物减少培养的HeLa S3细胞中具有靶突变的mtDNA。PIP靶向不同序列的可编程性可以使这类化合物在未来的研究中被开发为靶向与线粒体疾病相关的致病性突变的设计药物。
Mutations in mitochondrial DNA (mtDNA) cause mitochondrial diseases, characterized by abnormal mitochondrial function. Although eliminating mutated mtDNA has potential to cure mitochondrial diseases, no chemical-based drugs in clinical trials are capable of selective modulation of mtDNA mutations. Here, we construct a class of compounds encompassing pyrrole-imidazole polyamides (PIPs), mitochondria-penetrating peptide, and chlorambucil, an adenine-specific DNA-alkylating reagent. The sequence-selective DNA binding of PIPs allows chlorambucil to alkylate mutant adenine more efficiently than other sites in mtDNA.In vitroDNA alkylation assay shows that our compound8950A-Chb(Cl/OH)targeting a nonpathogenic point mutation in HeLa S3 cells (m.8950G>A) can specifically alkylate the mutant adenine. Furthermore, the compound reduces the mtDNA possessing the target mutation in cultured HeLa S3 cells. The programmability of PIPs to target different sequences could allow this class of compounds to be developed as designer drugs targeting pathogenic mutations associated with mitochondrial diseases in future studies.