2026-09-22T14:10:07Z https://www.ideals.illinois.edu/oai-pmh

oai:www.ideals.illinois.edu:2142/44815 2023-07-11 col_2142_5131 col_2142_14828 com_2142_5130 com_2142_14827 com_2142_14793 com_2142_8903

Zimmerman, Steven C. Zimmerman, Steven C. Spies, Maria Hergenrother, Paul J. Martinis, Susan A. Haghighat Jahromi, Amin 2013-05-28T19:21:02Z 2013-05-28T19:21:02Z 2015-05-28T10:02:17Z 2013-05 2013-05-28T19:21:02Z 2013-05 Myotonic dystrophy type 1 (DM1) is caused by an expanded CUG repeat (CUGexp) that sequesters muscleblind-like 1 protein (MBNL1), a protein that regulates alternative splicing. CUGexp RNA is a validated drug target for this currently untreatable disease. Herein, we describe the development of a bioactive small molecule (Chapter 2) and a small library of dimeric ligands (Chapter 3) leading to an optimized bivalent ligand. These novel ligands target CUGexp RNA and are able to inhibit the CUGexp⋅MBNL1 interaction in cells that model DM1. In a DM1 cell model these ligands were found to disperse CUGexp ribonuclear foci, release MBNL1, and partially reverse the mis-splicing of the insulin receptor pre-mRNA. Direct evidence for ribonuclear foci dispersion by this ligand was obtained in a live DM1 cell model using time-lapse confocal microscopy. In Chapter 4, We report a single-molecule approach to study the binding of MBNL1 to (CUG)n=4,6 and the effect of small molecules on this interaction. MBNL1 is able to bind to the (CUG)n･inhibitor complex indicating that the inhibition is not a straight forward competitive process. A simple bivalent ligand, shows a binding to (CUG)n almost 50-fold more tightly than the corresponding monomeric ligand and is more effective in destabilizing MBNL1･(CUG)4. The single-molecule method and the analysis framework might be extended to the study of other biomolecular interactions. Chapter 5 includes a preliminary effort to solve the mystery of CUGexp unfolding/folding upon interaction with MBNL1. To approach this unanswered yet key structural question about how MBNL1 binds CUGexp, preliminary bulk FRET (Fluorescence Resonance Energy Transfer) studies, as well as single-molecule FRET studies are described Item withdrawn by Mark Zulauf (zulauf@illinois.edu) on 2013-04-14T19:09:43Z Item was in collections: University of Illinois Theses & Dissertations (ID: 1) No. of bitstreams: 1 Haghighat Jahromi_Amin.pdf: 11909887 bytes, checksum: f03ec12f5efc4ab3652ced4b7b4b9538 (MD5) Made available in DSpace on 2013-05-28T19:21:02Z (GMT). No. of bitstreams: 2 Amin_Haghighat Jahromi.pdf: 11909004 bytes, checksum: b5892069ef93310c8c49a70185ced229 (MD5) license.txt: 4072 bytes, checksum: c3f191e6c04a468f959c59cf68e6b7d5 (MD5) Item marked as restricted to the 'Administrator' Group (id=1) by Seth Robbins (srobbins@illinois.edu) on 2013-05-28T19:22:06Z Item is restricted until 2015-05-28T19:21:22Z Restriction data tranferred 2014-07-01T11:17:30-05:00 Original Data Group with Access Administrator Release Date: 2015-05-28 14:21:22 UTC Reason: Author requested closed access (OA after 2yrs) in Vireo ETD system Limited Restriction Lifted for Item 44790 on 2015-05-28T10:02:17Z. http://hdl.handle.net/2142/44815 en Copyright Amin Haghighat Jahromi 2013 Myotonic Dystrophy Drug discovery MBNL1-CUGexp interaction Advances in myotonic dystrophy type 1 drug discovery through design of novel ligands and mechanism establishment text Dissertation School of Molecular & Cell Bio 1415 Biophysics & Computnl Biology 0319 University of Illinois at Urbana-Champaign Ph.D. PHD:Biophys&Computnl Bio -UIUC 10KS0319PHD