TY - JOUR
T1 - A Small Molecule that Binds an RNA Repeat Expansion Stimulates Its Decay via the Exosome Complex
AU - Angelbello, Alicia J.
AU - Benhamou, Raphael I.
AU - Rzuczek, Suzanne G.
AU - Choudhary, Shruti
AU - Tang, Zhenzhi
AU - Chen, Jonathan L.
AU - Roy, Madhuparna
AU - Wang, Kye Won
AU - Yildirim, Ilyas
AU - Jun, Albert S.
AU - Thornton, Charles A.
AU - Disney, Matthew D.
N1 - Funding Information: We thank J. Childs-Disney for experimental advice and Professor Denis Furling (Center de Recherche en Myologie [UPMC/Inserm/CNRS], Institut de Myologie) for his generous gift of myotube cell lines used in this paper. We also thank the agencies that funded this work, including the National Institutes of Health (DP1-NS096898 and R35 NS116846 to M.D.D. F31 NS110269 to A.J.A. and P50-NS048843 to C.A.T.), the Muscular Dystrophy Association (grant 380467 to M.D.D.), a Myotonic US Fellowship Research grant (to R.I.B. and S.C.), and a National Ataxia Foundation fellowship research grant (to R.I.B.). M.D.D. directed the study, conceived the idea, and designed experiments. A.J.A. R.I.B. and S.G.R. designed experiments, synthesized compounds, and conducted biochemical and cellular studies. S.C. J.L.C. K.W.W. and I.Y. performed modeling studies. Z.T. and C.A.T. performed experiments in mice. M.P. and A.S.J. provided cell lines. M.D.D. is a founder of Expansion Therapeutics, and S.G.R. and A.J.A. are currently employees of Expansion Therapeutics. M.D.D. and S.G.R. also have a patent related to this work (US20190152924A1). Funding Information: We thank J. Childs-Disney for experimental advice and Professor Denis Furling (Center de Recherche en Myologie [UPMC/Inserm/CNRS], Institut de Myologie) for his generous gift of myotube cell lines used in this paper. We also thank the agencies that funded this work, including the National Institutes of Health ( DP1-NS096898 and R35 NS116846 to M.D.D., F31 NS110269 to A.J.A., and P50-NS048843 to C.A.T.), the Muscular Dystrophy Association (grant 380467 to M.D.D.), a Myotonic US Fellowship Research grant (to R.I.B. and S.C.), and a National Ataxia Foundation fellowship research grant (to R.I.B.). Publisher Copyright: © 2020 Elsevier Ltd
PY - 2021/1/21
Y1 - 2021/1/21
N2 - Many diseases are caused by toxic RNA repeats. Herein, we designed a lead small molecule that binds the structure of the r(CUG) repeat expansion [r(CUG)exp] that causes myotonic dystrophy type 1 (DM1) and Fuchs endothelial corneal dystrophy (FECD) and rescues disease biology in patient-derived cells and in vivo. Interestingly, the compound's downstream effects are different in the two diseases, owing to the location of the repeat expansion. In DM1, r(CUG)exp is harbored in the 3′ untranslated region, and the compound has no effect on the mRNA's abundance. In FECD, however, r(CUG)exp is located in an intron, and the small molecule facilitates excision of the intron, which is then degraded by the RNA exosome complex. Thus, structure-specific, RNA-targeting small molecules can act disease specifically to affect biology, either by disabling the gain-of-function mechanism (DM1) or by stimulating quality control pathways to rid a disease-affected cell of a toxic RNA (FECD).
AB - Many diseases are caused by toxic RNA repeats. Herein, we designed a lead small molecule that binds the structure of the r(CUG) repeat expansion [r(CUG)exp] that causes myotonic dystrophy type 1 (DM1) and Fuchs endothelial corneal dystrophy (FECD) and rescues disease biology in patient-derived cells and in vivo. Interestingly, the compound's downstream effects are different in the two diseases, owing to the location of the repeat expansion. In DM1, r(CUG)exp is harbored in the 3′ untranslated region, and the compound has no effect on the mRNA's abundance. In FECD, however, r(CUG)exp is located in an intron, and the small molecule facilitates excision of the intron, which is then degraded by the RNA exosome complex. Thus, structure-specific, RNA-targeting small molecules can act disease specifically to affect biology, either by disabling the gain-of-function mechanism (DM1) or by stimulating quality control pathways to rid a disease-affected cell of a toxic RNA (FECD).
KW - RNA
KW - RNA splicing
KW - chemical biology
KW - decay pathways
KW - drug discovery
KW - microsatellite disorders
KW - targeted degradation
UR - http://www.scopus.com/inward/record.url?scp=85097059812&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.chembiol.2020.10.007
DO - https://doi.org/10.1016/j.chembiol.2020.10.007
M3 - Article
C2 - 33157036
SN - 2451-9456
VL - 28
SP - 34-45.e6
JO - Cell Chemical Biology
JF - Cell Chemical Biology
IS - 1
ER -