{"id":{"repo_id":"uiuc","oai_identifier":"oai:www.ideals.illinois.edu:2142/44815"},"canonical_url":"https://search.dev.ndltd.org/etd/uiuc/oai:www.ideals.illinois.edu:2142/44815","repository":{"repo_id":"uiuc","name":"University of Illinois - Urbana-Champaign","base_url":"https://www.ideals.illinois.edu/oai-pmh"},"display":{"title":"Advances in myotonic dystrophy type 1 drug discovery through design of novel ligands and mechanism establishment","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","abstract_html":"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","abstract_has_math":false,"creators":["Haghighat Jahromi, Amin"],"institution":"University of Illinois at Urbana-Champaign","degree_name":"Ph.D.","degree_level":"Dissertation","degree_discipline":"Biophysics & Computnl Biology","degree_department":null,"school":null,"contributors":["Zimmerman, Steven C.","Spies, Maria","Hergenrother, Paul J.","Martinis, Susan A."],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2013,"date_issued":"2013-05-28T19:21:02Z","date_published":"2013-05-28T19:21:02Z","updated_at":"2026-07-22T22:25:34Z","subjects":["Myotonic Dystrophy","Drug discovery","MBNL1-CUGexp interaction"],"languages":["en"],"rights":["Copyright Amin Haghighat Jahromi 2013"],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"http://hdl.handle.net/2142/44815","outbound_label":"Handle","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Zimmerman, Steven C.","Spies, Maria","Hergenrother, Paul J.","Martinis, Susan A."]},{"key":"dc:creator","label":"Author","values":["Haghighat Jahromi, Amin"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2013-05-28T19:21:02Z","2015-05-28T10:02:17Z","2013-05"]},{"key":"dc:type","label":"Dc Type","values":["text"]},{"key":"thesis:degree_discipline","label":"Discipline","values":["Biophysics & Computnl Biology"]},{"key":"thesis:degree_level","label":"Degree Level","values":["Dissertation"]},{"key":"thesis:degree_name","label":"Degree Name","values":["Ph.D."]},{"key":"thesis:institution_name","label":"Thesis Institution Name","values":["University of Illinois at Urbana-Champaign"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Myotonic Dystrophy","Drug discovery","MBNL1-CUGexp interaction"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["en"]},{"key":"dc:rights","label":"Dc Rights","values":["Copyright Amin Haghighat Jahromi 2013"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["http://hdl.handle.net/2142/44815"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description","label":"Description","values":["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. 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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). 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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). 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