Why the study?
Expanded RNA repeats cause over 30 incurable diseases, prompting approaches using small molecules that assemble into potent oligomers upon binding toxic RNA in cells.
In situ synthesis of an RNA-templated inhibitor significantly enhances potency against DM1-associated defects and enables visualization of the disease-causing RNA repeat.
May accelerate DM1 drug discovery; leaves open clinical translation from animal models.
Expanded RNA repeats cause more than 30 incurable diseases. One approach to mitigate their toxicity is by using small molecules that assemble into potent, oligomeric species upon binding to the disease-causing RNA in cells. Herein, we show that the expanded repeat [r(CUG) exp ] that causes myotonic dystrophy type 1 (DM1) catalyzes the in situ synthesis of its own inhibitor using an RNA-templated tetrazine ligation in DM1 patient-derived cells. The compound synthesized on-site improved DM1-associated defects at picomolar concentrations, enhancing potency by 10 000-fold, compared to its parent compounds that cannot undergo oligomerization. A fluorogenic reaction is also described where r(CUG) exp templates the synthesis of its own imaging probe to enable visualization of the repeat in its native context in live cells and muscle tissue.
No takes yet. Share an insight, caveat, or question.
Angelbello et al. (2020) studied this question.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: