{"id":{"repo_id":"uiuc","oai_identifier":"oai:www.ideals.illinois.edu:2142/90730"},"canonical_url":"https://search.dev.ndltd.org/etd/uiuc/oai:www.ideals.illinois.edu:2142/90730","repository":{"repo_id":"uiuc","name":"University of Illinois - Urbana-Champaign","base_url":"https://www.ideals.illinois.edu/oai-pmh"},"display":{"title":"Design, synthesis, and biological activities of small molecules that target myotonic dystrophy","abstract":"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.","abstract_html":"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.","abstract_has_math":false,"creators":["Nguyen, Lien Thi Thuy"],"institution":"University of Illinois at Urbana-Champaign","degree_name":"Ph.D.","degree_level":"Dissertation","degree_discipline":"Chemistry","degree_department":null,"school":null,"contributors":["Zimmerman, Steven C.","Hergenrother, Paul J.","Katzenellenbogen, John A.","Oldfield, Eric"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2016,"date_issued":"2016-07-07T20:27:00Z","date_published":"2016-07-07T20:27:00Z","updated_at":"2026-07-22T22:26:34Z","subjects":["Myotonic Dystrophy","Drug development"],"languages":["en"],"rights":["Copyright 2016 Lien Nguyen"],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"http://hdl.handle.net/2142/90730","outbound_label":"Handle","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Zimmerman, Steven C.","Hergenrother, Paul J.","Katzenellenbogen, John A.","Oldfield, Eric"]},{"key":"dc:creator","label":"Author","values":["Nguyen, Lien Thi Thuy"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2016-07-07T20:27:00Z","2018-07-08T09:15:23Z","2016-04-01","2016-05"]},{"key":"dc:type","label":"Dc Type","values":["text"]},{"key":"thesis:degree_discipline","label":"Discipline","values":["Chemistry"]},{"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 development"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["en"]},{"key":"dc:rights","label":"Dc Rights","values":["Copyright 2016 Lien Nguyen"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["http://hdl.handle.net/2142/90730"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description","label":"Description","values":["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.","Submission published under a 24 month embargo labeled 'U of I Access', the embargo will last until 2018-05-01","The student, Lien Nguyen, accepted the attached license on 2016-03-19 at 15:58.","The student, Lien Nguyen, submitted this Dissertation for approval on 2016-03-19 at 16:08.","This Dissertation was approved for publication on 2016-04-01 at 10:22.","DSpace SAF Submission Ingestion Package generated from Vireo submission #9114 on 2016-07-07 at 13:48:37","Made available in DSpace on 2016-07-07T20:27:00Z (GMT). No. of bitstreams: 3 NGUYEN-DISSERTATION-2016.pdf: 6601452 bytes, checksum: d66f56c2df2842892d64e62616b3c4cd (MD5) LICENSE.txt: 4208 bytes, checksum: 107ccc36d298ff20e792c9db1c610fbd (MD5) PROQUEST_LICENSE.txt: 4554 bytes, checksum: 37de2d19a442dc3b72f09d64ff61861a (MD5) Previous issue date: 2016-04-01","Embargo set by: Seth Robbins for item 93082 Lift date: 2018-07-07T20:28:14Z Reason: Author requested U of Illinois access only (OA after 2yrs) in Vireo ETD system","Embargo set by: Seth Robbins for item 93082 Lift date: 2018-07-07T20:35:34Z Reason: Author requested U of Illinois access only (OA after 2yrs) in Vireo ETD system","U of I Only Restriction Lifted for Item 93082 on 2018-07-08T09:15:23Z."]},{"key":"dc:format","label":"Dc Format","values":["application/pdf"]},{"key":"dc:title","label":"Title","values":["Design, synthesis, and biological activities of small molecules that target myotonic dystrophy"]}]}],"canonical_facts":{"dc:contributor":["Zimmerman, Steven C.","Hergenrother, Paul J.","Katzenellenbogen, John A.","Oldfield, Eric"],"dc:creator":["Nguyen, Lien Thi Thuy"],"dc:date":["2016-07-07T20:27:00Z","2018-07-08T09:15:23Z","2016-04-01","2016-05"],"dc:description":["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.","Submission published under a 24 month embargo labeled 'U of I Access', the embargo will last until 2018-05-01","The student, Lien Nguyen, accepted the attached license on 2016-03-19 at 15:58.","The student, Lien Nguyen, submitted this Dissertation for approval on 2016-03-19 at 16:08.","This Dissertation was approved for publication on 2016-04-01 at 10:22.","DSpace SAF Submission Ingestion Package generated from Vireo submission #9114 on 2016-07-07 at 13:48:37","Made available in DSpace on 2016-07-07T20:27:00Z (GMT). No. of bitstreams: 3 NGUYEN-DISSERTATION-2016.pdf: 6601452 bytes, checksum: d66f56c2df2842892d64e62616b3c4cd (MD5) LICENSE.txt: 4208 bytes, checksum: 107ccc36d298ff20e792c9db1c610fbd (MD5) PROQUEST_LICENSE.txt: 4554 bytes, checksum: 37de2d19a442dc3b72f09d64ff61861a (MD5) Previous issue date: 2016-04-01","Embargo set by: Seth Robbins for item 93082 Lift date: 2018-07-07T20:28:14Z Reason: Author requested U of Illinois access only (OA after 2yrs) in Vireo ETD system","Embargo set by: Seth Robbins for item 93082 Lift date: 2018-07-07T20:35:34Z Reason: Author requested U of Illinois access only (OA after 2yrs) in Vireo ETD system","U of I Only Restriction Lifted for Item 93082 on 2018-07-08T09:15:23Z."],"dc:format":["application/pdf"],"dc:identifier":["http://hdl.handle.net/2142/90730"],"dc:language":["en"],"dc:rights":["Copyright 2016 Lien Nguyen"],"dc:subject":["Myotonic Dystrophy","Drug development"],"dc:title":["Design, synthesis, and biological activities of small molecules that target myotonic dystrophy"],"dc:type":["text"],"thesis:degree_discipline":["Chemistry"],"thesis:degree_level":["Dissertation"],"thesis:degree_name":["Ph.D."],"thesis:institution_name":["University of Illinois at Urbana-Champaign"]},"updated_at":"2026-07-22T22:26:34Z"}