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Zimmerman, Steven C. Zimmerman, Steven C. Hergenrother, Paul J. White, M. Christina Kalsotra, Auinash Luu, Long Minh 2017-03-01T17:01:01Z 2017-03-01T17:01:01Z 2019-03-02T10:15:33Z 2016-10-24 2016-12 Myotonic dystrophy type 1 (DM1), the most common form of adult-onset muscular dystrophy, is an incurable neuromuscular disease. DM1 is caused by an expansion of the CTG repeat, whose RNA transcript sequesters the MBNL1 protein into nuclear foci, leading to the misregulation of various pre-mRNAs. Based on a published x-ray structure of a r(CUG)6 hairpin, a benzamidinium ligand was rationally designed and found to selectively bind rCUG repeats and inhibit the MBNL1-rCUGexp interaction with a low micro-molar inhibition potency. Thus, this bisamidinium RNA groove binder represented one of the most promising lead compounds for DM1 treatment. The development of the bisamidinium analogs containing functional substituents will be discussed in Chapter 2. Chapter 3 describes the development of a bisamidinium dimeric ligand as a possible compound for the treatment of DM1. This ligand reveals both the promise and challenge for the small molecule approach. The agent is a potent inhibitor of the MBNL1-rCUGexp both in vitro and in DM1 model cells, and is able to improve two distinct disease phenotypes in a DM1 Drosophila model. However, its relatively low maximum tolerated dose in mice and limited cell uptake provide insights into directions for future development. In addition, a powerful selection method that uses the target DNA or RNA to select their own binders will be discussed in Chapter 4. Compounds discovered using this method are able to undergo the alkyne-azide cycloaddition on the target DNA and RNA. The selectivity of these compounds along with their click products to other DNA/RNA sequences can also be readily accessed. The click products formed have better efficacy and can be used as multi-target agents. Submission published under a 24 month embargo labeled 'Closed Access', the embargo will last until 2018-12-01 The student, Long Luu, accepted the attached license on 2016-10-19 at 23:26. The student, Long Luu, submitted this Dissertation for approval on 2016-10-19 at 23:39. This Dissertation was approved for publication on 2016-10-24 at 10:39. DSpace SAF Submission Ingestion Package generated from Vireo submission #10200 on 2017-02-28 at 14:41:01 Made available in DSpace on 2017-03-01T17:01:01Z (GMT). No. of bitstreams: 2 LUU-DISSERTATION-2016.pdf: 33521366 bytes, checksum: ea0cc4d498ab9c9e947cceee31881321 (MD5) LICENSE.txt: 4205 bytes, checksum: 628818192280c8605468515f55019032 (MD5) Previous issue date: 2016-10-24 Embargo set by: Seth Robbins for item 98671 Lift date: 2019-03-01T17:02:22Z Reason: Author requested closed access (OA after 2yrs) in Vireo ETD system Embargo set by: Seth Robbins for item 98671 Lift date: 2019-03-01T17:03:32Z Reason: Author requested closed access (OA after 2yrs) in Vireo ETD system Embargo set by: Seth Robbins for item 98671 Lift date: 2019-03-01T17:05:02Z Reason: Author requested closed access (OA after 2yrs) in Vireo ETD system Embargo set by: Seth Robbins for item 98671 Lift date: 2019-03-01T17:06:55Z Reason: Author requested closed access (OA after 2yrs) in Vireo ETD system Limited Restriction Lifted for Item 98671 on 2019-03-02T10:15:33Z. application/pdf http://hdl.handle.net/2142/95555 en Copyright 2016 Long Luu Myotonic Dystrophy RNA binder Click chemistry Approaches to the assembly of potent therapeutic agents for the treatment of myotonic dystrophy text text Chemistry Chemistry University of Illinois at Urbana-Champaign Dissertation Ph.D.