Design, synthesis, and biological activities of small molecules that target myotonic dystrophy

Myotonic dystrophy (DM) is a triple-repeat expansion, multi-systemic disease that affects one in eight thousand people worldwide. The cause of the disease is a progressive, abnormal expansion of CTG repeats (CUGexp) in the 3'-UTR of the DMPK gene (DM1) and CCTG repeats (CCUGexp) in the intron 1 of the ZNP9 gene (DM2). The sequestration of muscleblind-like proteins (MBNL) by CUGexp or CCUGexp causes splicing defects in more than 100 pre-mRNAs, resulting in various disease phenotypes. As such, therapeutic development for DM has mainly focused on agents targeting the CUGexp/CCUGexp -MBNL1 interaction. This dissertation focuses on the development of rationally designed small molecules that target CUGexp and CCUGexp, including their synthesis and studies of their biological activity. The background of DM with a focus on its molecular mechanism and various therapeutic approaches are reviewed in Chapter 1. Chapter 2 includes the story of how simple ligands targeting CUGexp have been developed and investigations of the biological activity of acridine-based and bisamidinium-based ligands synthesized by others in our group. Chapter 3 focuses on the design, synthesis, and biological activity of bisamidinium-based ligands that target CCUGexp. Because other toxic pathways, including microRNA dysregulation in DM1 heart tissue and the production of polypeptides via repeat-associated non-ATG translation, are induced by CUGexp, recent efforts on DM1 therapeutic approaches have moved beyond just preventing the formation of CUGexp-MBNL1 complex and further focused on regulating the level of toxic CUGexp. Thus, Chapter 4 discusses a multi-target approach for DM1 in which a ligand with a RNA-cleaving unit can bind both CTGexp and CUGexp and regulate the level of CUGexp.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Chemistry

Grantor

University of Illinois at Urbana-Champaign

Year dc:date

2016

Author dc:creator

• Nguyen, Lien Thi Thuy

Contributors dc:contributor

• Zimmerman, Steven C.
• Hergenrother, Paul J.
• Katzenellenbogen, John A.
• Oldfield, Eric

• Myotonic Dystrophy
• Drug development

Statement dc:rights

• Copyright 2016 Lien Nguyen

Language dc:language

en

Handle dc:identifier

http://hdl.handle.net/2142/90730

OAI identifier oai:identifier

oai:www.ideals.illinois.edu:2142/90730