A Ligand That Targets CUG Trinucleotide Repeats

Abstract

The development of small molecules that can recognize specific RNA secondary and tertiary structures is currently an important research topic for developing tools to modulate gene expression and therapeutic drugs. Expanded CUG trinucleotide repeats, known as toxic RNA, capture the splicing factor MBNL1 and are causative of neurological disorder myotonic dystrophy type 1 (DM1). Herein, the rational molecular design, synthesis, and binding analysis of 2,9-diaminoalkyl-substituted 1,10-phenanthroline (DAP), which bound to CUG trinucleotide repeats, is described. The results of melting temperature (T_m ) analyses, surface plasmon resonance (SPR) assay, and electrospray spray ionization time-of-flight (ESI-TOF) mass spectrometry showed that DAP bound to r(CUG)₉ but not to r(CAG)₉ and r(CGG)₉ . The dual luciferase assay clearly indicated DAP bound to the r(CUG)_n repeat by affecting the translation in vitro.

Keywords: (CUG)n repeats; RNA; SPR; small molecules; translation.