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Biological Chemistry

Designer molecule silences mitochondrial genes

Peptidelike molecule passes through mitochondrial double membrane to turn off genes

by Erika Gebel Berg, special to C&EN
July 24, 2017 | A version of this story appeared in Volume 95, Issue 30

Mitochondria are like miniature fortresses. Getting synthetic chemicals past this organelle’s formidable double membrane isn’t easy. As a result, scientists haven’t yet developed drugs that target the biology underlying mitochondrial disorders, which can be deadly.

Credit: Ganesh N. Pandian
This molecule can penetrate mitochondrial membranes and silence genes.
Model of mitochondria-penetrating peptide conjugated to a pyrrole-imidazole polyamide.
Credit: Ganesh N. Pandian
This molecule can penetrate mitochondrial membranes and silence genes.

Now, researchers have developed a peptidelike molecule that penetrates the mitochondrial membrane to inhibit the expression of a gene associated with nerve and muscle diseases (J. Am. Chem. Soc. 2017, DOI: 10.1021/jacs.7b05230).

In the past couple of decades, scientists have developed compounds called pyrrole-imidazole polyamides (PIPs) to modify gene expression in cells. These peptidelike polymers consist of nonnatural amino acids with pyrrole or imidazole rings. Researchers can use PIPs as a tool for silencing genes by designing the sequence of amino acids to target and bind to specific stretches of DNA. When such agents target the promoter region of a gene, they block a transcription factor from binding and starting gene expression.

Ganesh N. Pandian and Hiroshi Sugiyama of Kyoto University, along with their colleagues, linked a PIP designed to bind to the promoter region of ND6—a gene associated with several mitochondrial disorders—to a peptide designed to pass through the mitochondrial membrane. The peptide combines lipophilic amino acids, which aid passage through the membrane, with positively charged amino acids, which target the negatively charged interior of mitochondria, where gene expression happens.

The researchers added the agent to a culture of human cancer cells, and after 24 hours, ND6 expression levels were 90% lower compared with untreated cells. Cells given the PIP without the mitochondria-penetrating peptide showed no change in ND6 levels.

“This paper brought a big smile to my face because it’s something I never thought of,” says Joel M. Gottesfeld of Scripps Research Institute California. “In fact, I’ve never heard of targeting mitochondrial transcription by any means.” Mitochondria present a huge drug delivery challenge, so small molecules such as PIPs show a lot of potential, he adds.



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