University of Illinois Urbana-Champaign

Advances in myotonic dystrophy type 1 drug discovery through design of novel ligands and mechanism establishment

Haghighat Jahromi, Amin

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Amin_Haghighat Jahromi.pdf

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https://hdl.handle.net/2142/44815

Description

Title
Advances in myotonic dystrophy type 1 drug discovery through design of novel ligands and mechanism establishment
Author(s)
Haghighat Jahromi, Amin
Issue Date
2013-05-28T19:21:02Z
Director of Research (if dissertation) or Advisor (if thesis)
Zimmerman, Steven C.
Doctoral Committee Chair(s)
Zimmerman, Steven C.
Committee Member(s)
  • Spies, Maria
  • Hergenrother, Paul J.
  • Martinis, Susan A.
Department of Study
School of Molecular & Cell Bio
Discipline
Biophysics & Computnl Biology
Degree Granting Institution
University of Illinois at Urbana-Champaign
Degree Name
Ph.D.
Degree Level
Dissertation
Date of Ingest
2013-05-28T19:21:02Z
Keyword(s)
  • Myotonic Dystrophy
  • Drug discovery
  • MBNL1-CUGexp interaction
Abstract
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
Graduation Semester
2013-05
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http://hdl.handle.net/2142/44815
Copyright and License Information
Copyright Amin Haghighat Jahromi 2013

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