التفاصيل البيبلوغرافية
| العنوان: |
En Route to Targeted Ribosome Editing to Replenish Skin Anchor Protein LAMB3 in Junctional Epidermolysis Bullosa |
| المؤلفون: |
Wimmer, Bjoern, Friedrich, Andreas, Poeltner, Katharina, Edobor, Genevieve, Mosshammer, Claudia, Temaj, Gazmend, Rathner, Adriana, Karl, Thomas, Krauss, Jan, von Hagen, Joerg, Gerner, Christopher, Breitenbach, Michael, Hintner, Helmut, Bauer, Johannes W., Breitenbach-Koller, Hannelore |
| المصدر: |
JID Innovations; 20230101, Issue: Preprints |
| مستخلص: |
Severe junctional epidermolysis bullosa is a rare genetic, postpartum lethal skin disease, predominantly caused by nonsense/premature termination codon (PTC) mutations in LAMB3gene. LAMB3encodes LAMB3, the β subunit of epidermal–dermal skin anchor laminin 332. Most translational reads of a PTC mRNA deliver truncated, nonfunctional proteins, whereas an endogenous PTC readthrough mechanism produces full-length protein at minimal and insufficient levels. Conventional translational readthrough-inducing drugs amplify endogenous PTC readthrough; however, translational readthrough-inducing drugs are either proteotoxic or nonselective. Ribosome editing is a more selective and less toxic strategy. This technique identified ribosomal protein L35/uL29 (ie, RpL35) and RpL35-ligands repurposable drugs artesunate and atazanavir as molecular tools to increase production levels of full-length LAMB3. To evaluate ligand activity in living cells, we monitored artesunate and atazanavir treatment by dual luciferase reporter assays. Production levels of full-length LAMB3 increased up to 200% upon artesunate treatment, up to 150% upon atazanavir treatment, and up to 170% upon combinatorial treatment of RpL35 ligands at reduced drug dosage, with an unrelated PTC reporter being nonresponsive. Proof of bioactivity of RpL35 ligands in selective increase of full-length LAMB3 provides the basis for an alternative, targeted therapeutic route to replenish LAMB3 in severe junctional epidermolysis bullosa. |
| قاعدة البيانات: |
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