As people well know PROTAC(PROteolysis TArgeting Chimeras) is one of the interesting approach for targeted protein degradation. It has warhead, ligand of targeted protein and ligand of E3 ligase. This bi-functional molecule motif ‘A-Linker-B’ is widely used in drug design. And I read a very interesting article found in my twitter TL. The URL is shown below. It’s open access!!!
https://science.sciencemag.org/content/358/6370/1617
The author targeted cell line derived from a Friedreich’s ataxia patient. In this cell line, GAA triplet repeat cause lack of frataxin (FXN). Their compound design strategy is ….
Combine BRD4 inhibitor JQ-1 and GAA specific molecule which has pyrrole-imidazole based polyamide which linker (called Syn-TEF in the article). < JQ-1 -Linker- pyrrole-imidazole poly amide >
The designed molecule binds specific region of DNA and recruits BRD4 then Pol II elongate DNA and FXN mRNA will be expressed. The workflow is shown in Fig2-F. It’s well designed process.
In the Fig1-C shows specificity of the molecule between normal and disease cell. Normal cell has < 30 GAA repeats, disease cell has > 650 GAA repeats and Syn-TEF poly pyrrole-imidazole can only bind long GAA repeats. The relative FXN mRNA with syn-TEF increased in left ( Fig 1C, has rich GAA repeats ) but doesn’t increased in right (Fig 1C). That means Syn-TEF can target for abnormal cell and not affect normal cell. Finally the group showed in vivo bioluminescent imaging study. In this study Syn-TEF treated mouse showed higher expression of FXN.
Their results shows possibility of control gene expression of targeted gene. Will the strategy be new modality of drug design. I’m looking forward to reading progress of the research near the feature.
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