RRC ID 69796
Author Shibata T, Nagano K, Ueyama M, Ninomiya K, Hirose T, Nagai Y, Ishikawa K, Kawai G, Nakatani K.
Title Small molecule targeting r(UGGAA)n disrupts RNA foci and alleviates disease phenotype in Drosophila model.
Journal Nat Commun
Abstract Synthetic small molecules modulating RNA structure and function have therapeutic potential for RNA diseases. Here we report our discovery that naphthyridine carbamate dimer (NCD) targets disease-causing r(UGGAA)n repeat RNAs in spinocerebellar ataxia type 31 (SCA31). Structural analysis of the NCD-UGGAA/UGGAA complex by nuclear magnetic resonance (NMR) spectroscopy clarifies the mode of binding that recognizes four guanines in the UGGAA/UGGAA pentad by hydrogen bonding with four naphthyridine moieties of two NCD molecules. Biological studies show that NCD disrupts naturally occurring RNA foci built on r(UGGAA)n repeat RNA known as nuclear stress bodies (nSBs) by interfering with RNA-protein interactions resulting in the suppression of nSB-mediated splicing events. Feeding NCD to larvae of the Drosophila model of SCA31 alleviates the disease phenotype induced by toxic r(UGGAA)n repeat RNA. These studies demonstrate that small molecules targeting toxic repeat RNAs are a promising chemical tool for studies on repeat expansion diseases.
Volume 12(1)
Pages 236
Published 2021-1-11
DOI 10.1038/s41467-020-20487-4
PII 10.1038/s41467-020-20487-4
PMID 33431896
PMC PMC7801683
MeSH Animals Base Sequence Cell Nucleus / metabolism Disease Models, Animal Drosophila / genetics* HeLa Cells Humans Introns / genetics Magnetic Resonance Spectroscopy Models, Molecular Nucleic Acid Conformation Phenotype Phosphorylation RNA / genetics* RNA-Binding Proteins / metabolism Small Molecule Libraries / pharmacology Temperature
IF 12.121
Human and Animal Cells HeLa(RCB0007)