Cell Chemical Biology
Volume 29, Issue 4, 21 April 2022, Pages 690-695.e5
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Brief Communication
Targeted elimination of mutated mitochondrial DNA by a multi-functional conjugate capable of sequence-specific adenine alkylation

https://doi.org/10.1016/j.chembiol.2021.08.003Get rights and content
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Highlights

  • Sequence-selective mitochondrial DNA (mtDNA) alkylators have been developed

  • In vitro assays verified selective alkylation of mutant adenine in mtDNA sequence

  • Studies in live cells show a reduction of mutant mtDNA by our alkylator

  • Our strategy targeting mtDNA has therapeutic potential in mitochondrial diseases

Summary

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 vitro DNA alkylation assay shows that our compound 8950A-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.

Keywords

pyrrole-imidazole polyamide
mitochondrial DNA
mitochondria
DNA alkylation
DNA mutation
heteroplasmy
mitochondrial disease
designer small molecule

Data and code availability

Data reported in this paper will be shared by the lead contact upon request. This paper does not report original code. Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request.

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