Small molecule targeting r(UGGAA)n disrupts RNA foci and alleviates disease phenotype in Drosophila model

Tomonori Shibata, Konami Nagano, Morio Ueyama, Kensuke Ninomiya, Tetsuro Hirose, Yoshitaka Nagai, Kinya Ishikawa, Gota Kawai and Kazuhiko Nakatani ()
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Tomonori Shibata: The Institute of Scientific and Industrial Research (ISIR), Osaka University
Konami Nagano: Chiba Institute of Technology
Morio Ueyama: Osaka University Graduate School of Medicine
Kensuke Ninomiya: Osaka University
Tetsuro Hirose: Osaka University
Yoshitaka Nagai: Osaka University Graduate School of Medicine
Kinya Ishikawa: Tokyo Medical and Dental University
Gota Kawai: Chiba Institute of Technology
Kazuhiko Nakatani: The Institute of Scientific and Industrial Research (ISIR), Osaka University

Nature Communications, 2021, vol. 12, issue 1, 1-13

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-020-20487-4

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