The Dimeric Form of 1,3-Diaminoisoquinoline Derivative Rescued the Mis-splicing of Atp2a1 and Clcn1 Genes in Myotonic Dystrophy Type 1 Mouse Model.

Jun Matsumoto, Masayuki Nakamori, Tatsumasa Okamoto, Asako Murata, Chikara Dohno, Kazuhiko Nakatani

Chemistry (Weinheim an der Bergstrasse, Germany) 2020 Nov 11

filter terms:

Expanded CUG repeat RNA in the dystrophia myotonia protein kinase (DMPK) gene causes myotonic dystrophy type 1 (DM1) and sequesters RNA processing proteins, such as the splicing factor muscleblind-like 1 protein (MBNL1). Sequestration of splicing factors results in the mis-splicing of some pre-mRNAs. Small molecules that rescue the mis-splicing in the DM1 cells have drawn attention as potential drugs to treat DM1. Herein we report a new molecule JM642 consisted of two 1,3-diaminoisoquinoline chromophores having an auxiliary aromatic unit at the C5 position. JM642 alternates the splicing pattern of the pre-mRNA of the Ldb3 gene in the DM1 cell model and Clcn1 and Atp2a1 genes in the DM1 mouse model. In vitro binding analysis by surface plasmon resonance (SPR) assay to the r(CUG) repeat and disruption of ribonuclear foci in the DM1 cell model suggested the binding of JM642 to the expanded r(CUG) repeat in vivo, eventually rescue the mis-splicing. © 2020 The Authors. Published by Wiley-VCH GmbH.

Citation

Jun Matsumoto, Masayuki Nakamori, Tatsumasa Okamoto, Asako Murata, Chikara Dohno, Kazuhiko Nakatani. The Dimeric Form of 1,3-Diaminoisoquinoline Derivative Rescued the Mis-splicing of Atp2a1 and Clcn1 Genes in Myotonic Dystrophy Type 1 Mouse Model. Chemistry (Weinheim an der Bergstrasse, Germany). 2020 Nov 11;26(63):14305-14309