A newly synthesized compound may enhance the transcription of repressed frataxin (FXN) in Friedreich ataxia (FA) cells more effectively than the previously reported Syn-TEF1 compound, according to an article published in Bioorganic & Medicinal Chemistry.

Although the novel compound has low solubility in water and demonstrates cytotoxicity at high concentrations, 2-hydroxypropyl-β-cyclodextrin (HpβCD) may increase cell viability.

Researchers have previously reported that the N-terminal modifications of linear PIPs may increase their affinity to targeting dsDNA13. For this study, they synthesized Syn-TEF1 and 3 analogs of Syn-TEF1 and assessed their impact on FXN transcription.

Next, they administered the compounds to the lymphocyte cell line derived from a patient with FA and used real-time qPCR to gain insight into the promotion of the repressed FXN transcription. They also performed solubility and cytotoxicity assays.

According to the results, the first synthesized N-terminal modified analog (compound 2) had minimal ability to target DNA contributing to a higher cellular effect. Compound 3, with a diamine linker, was more effective than compound 2 but still less effective than Syn-TEF1.

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The study authors then synthesized a hydrophobic compound 1, which lacked N-terminal cationic modification and had the highest cellular effects among all 3 compounds. However, it was difficult to dissolve in water despite having intermolecular polyethylene glycol (PEG).

Compared with Syn-TEF1, compound 1 was more effective in only a tenth of the concentration, yet it demonstrated cytotoxicity in higher concentrations. Next, the researchers formulated 2-hydroxypropyl-β-cyclodextrin (HpβCD) to improve the solubility and slightly decrease the compound 1 cytotoxicity.

“The aggregation of amphiphilic compound 1 might be one of the reasons for induction of cell death. Dissolving the aggregation with a formulating reagent would be crucial in avoiding cell death,” Hatanaka and colleagues wrote.

Previously, Syn-TEF1 was reported to promote the transcription of FXN in isolated FA patient cells. The synthetic compound is made of (GAA)3-binding linear PIP, a class of oligopeptide that targets double-stranded DNA with sequence selectivity, PEG6 linker, and bromodomain inhibitor (+)-JQ1.


Hatanaka J, Hashiya K, Bando T, Sugiyama H. Substitution to hydrophobic linker and formation of host-guest complex enhanced the effect of synthetic transcription factor made of pyrrole-imidazole polyamideBioorg Med Chem. Published online February 9, 2023. doi:10.1016/j.bmc.2023.117208