{"id":{"repo_id":"uiuc","oai_identifier":"oai:www.ideals.illinois.edu:2142/99509"},"canonical_url":"https://search.dev.ndltd.org/etd/uiuc/oai:www.ideals.illinois.edu:2142/99509","repository":{"repo_id":"uiuc","name":"University of Illinois - Urbana-Champaign","base_url":"https://www.ideals.illinois.edu/oai-pmh"},"display":{"title":"Development of enforced stacked intercalators that target trinucleotide repeat mismatches in DNA","abstract":"Mismatched base pairs are ubiquitous in more than 30 hereditary disorders whose origin can be traced to unstable repeating sequences in genomic DNA. For instance, non-Watson– Crick T–T mismatch base pairs flanked by G–C base pairs appear in myotonic dystrophy type 1 (DM1), which is caused by the expansion of CTG trinucleotide repeats (TNR) in the 3’- untranslated region of the dystrophia myotonica protein kinase (DMPK) gene. Extensive efforts have made it possible to elucidate its pathogenesis and mechanism of action. In this regard, numerous compounds have been developed that target the toxic repeating CUG RNA transcript (r(CUG)exp) and inhibit its sequestration of key pre-mRNA splicing proteins, such as MBNL1. Indeed, since we reported our first ligand JFA in 2009, our group has been at the forefront in discovering ligands that specifically bind U–U mismatches and can potentially be used as therapeutics. More recently, we have started to focus our efforts to discover molecules that target the parent CTG expanded repeats (d(CTG)exp) in hopes to develop a more promising therapeutic. A brief overview of targeting DNA, DNA mismatches, DM1 and our ligands is given in Chapter 1. A previous anisotropy screen in our lab of ligands that inhibit the MBNL1–r(CUG)exp complex identified a novel lead pyrroloquinazoline compound. However, as we will see in Chapter 2, further investigation revealed that it was selective for T–T mismatches. Interestingly, we noted that mode of binding toward CTG mismatched sites appeared to be cooperative. Due to its limited water solubility, we attempted to develop further derivatives. We took into consideration these observations to develop and improve our acridine-base ligands in the last chapter. To further improve the affinity and selectivity of our acridine-based ligands, we proceeded to develop a series of enforced stacked intercalators. Our first approach involved utilizing a larger mismatch-recognition diaminopurine unit, as the described in the first part of Chapter 3. However, although selective for T–T and C–C mismatches, its nonspecific binding was not improved. Finally, we employed a macrocyclic design, and developed a small library of macrocycles. We showed that these ligands selectively bind to CTG trinucleotide repeats in DNA with negligible nonspecific binding to duplex DNA. In addition, they were about twice as effective and selective in inhibiting transcription than the control. Lastly, we discovered that the macrocyclic structure design of our ligands did not necessarily correlate with a reduction in their cytotoxicity in HeLa cells, as we had previously hypothesized. The synthesis, biophysical studies, and in vitro activity of these macrocyclic ligands are described in the second part of Chapter 3.","abstract_html":"Mismatched base pairs are ubiquitous in more than 30 hereditary disorders whose origin can be traced to unstable repeating sequences in genomic DNA. For instance, non-Watson– Crick T–T mismatch base pairs flanked by G–C base pairs appear in myotonic dystrophy type 1 (DM1), which is caused by the expansion of CTG trinucleotide repeats (TNR) in the 3’- untranslated region of the dystrophia myotonica protein kinase (DMPK) gene. Extensive efforts have made it possible to elucidate its pathogenesis and mechanism of action. In this regard, numerous compounds have been developed that target the toxic repeating CUG RNA transcript (r(CUG)exp) and inhibit its sequestration of key pre-mRNA splicing proteins, such as MBNL1. Indeed, since we reported our first ligand JFA in 2009, our group has been at the forefront in discovering ligands that specifically bind U–U mismatches and can potentially be used as therapeutics. More recently, we have started to focus our efforts to discover molecules that target the parent CTG expanded repeats (d(CTG)exp) in hopes to develop a more promising therapeutic. A brief overview of targeting DNA, DNA mismatches, DM1 and our ligands is given in Chapter 1. A previous anisotropy screen in our lab of ligands that inhibit the MBNL1–r(CUG)exp complex identified a novel lead pyrroloquinazoline compound. However, as we will see in Chapter 2, further investigation revealed that it was selective for T–T mismatches. Interestingly, we noted that mode of binding toward CTG mismatched sites appeared to be cooperative. Due to its limited water solubility, we attempted to develop further derivatives. We took into consideration these observations to develop and improve our acridine-base ligands in the last chapter. To further improve the affinity and selectivity of our acridine-based ligands, we proceeded to develop a series of enforced stacked intercalators. Our first approach involved utilizing a larger mismatch-recognition diaminopurine unit, as the described in the first part of Chapter 3. However, although selective for T–T and C–C mismatches, its nonspecific binding was not improved. Finally, we employed a macrocyclic design, and developed a small library of macrocycles. We showed that these ligands selectively bind to CTG trinucleotide repeats in DNA with negligible nonspecific binding to duplex DNA. In addition, they were about twice as effective and selective in inhibiting transcription than the control. Lastly, we discovered that the macrocyclic structure design of our ligands did not necessarily correlate with a reduction in their cytotoxicity in HeLa cells, as we had previously hypothesized. The synthesis, biophysical studies, and in vitro activity of these macrocyclic ligands are described in the second part of Chapter 3.","abstract_has_math":false,"creators":["Serrano, Julio Francisco"],"institution":"University of Illinois at Urbana-Champaign","degree_name":"Ph.D.","degree_level":"Dissertation","degree_discipline":"Chemistry","degree_department":null,"school":null,"contributors":["van der Donk, Wilfred A.","Zimmerman, Steven C.","Mitchell, Douglas A.","Huang, Raven H."],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2018,"date_issued":"2018-03-13T17:35:46Z","date_published":"2018-03-13T17:35:46Z","updated_at":"2026-07-22T22:24:37Z","subjects":["Macrocycle bisintercalator","Deoxyribonucleic acid (DNA) targeting","Small molecules"],"languages":["en"],"rights":["Copyright 2017 Julio F. 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Indeed, since we reported our first ligand JFA in 2009, our group has been at the forefront in discovering ligands that specifically bind U–U mismatches and can potentially be used as therapeutics. More recently, we have started to focus our efforts to discover molecules that target the parent CTG expanded repeats (d(CTG)exp) in hopes to develop a more promising therapeutic. A brief overview of targeting DNA, DNA mismatches, DM1 and our ligands is given in Chapter 1. A previous anisotropy screen in our lab of ligands that inhibit the MBNL1–r(CUG)exp complex identified a novel lead pyrroloquinazoline compound. However, as we will see in Chapter 2, further investigation revealed that it was selective for T–T mismatches. Interestingly, we noted that mode of binding toward CTG mismatched sites appeared to be cooperative. Due to its limited water solubility, we attempted to develop further derivatives. We took into consideration these observations to develop and improve our acridine-base ligands in the last chapter. To further improve the affinity and selectivity of our acridine-based ligands, we proceeded to develop a series of enforced stacked intercalators. Our first approach involved utilizing a larger mismatch-recognition diaminopurine unit, as the described in the first part of Chapter 3. However, although selective for T–T and C–C mismatches, its nonspecific binding was not improved. Finally, we employed a macrocyclic design, and developed a small library of macrocycles. We showed that these ligands selectively bind to CTG trinucleotide repeats in DNA with negligible nonspecific binding to duplex DNA. In addition, they were about twice as effective and selective in inhibiting transcription than the control. Lastly, we discovered that the macrocyclic structure design of our ligands did not necessarily correlate with a reduction in their cytotoxicity in HeLa cells, as we had previously hypothesized. The synthesis, biophysical studies, and in vitro activity of these macrocyclic ligands are described in the second part of Chapter 3.","Submission published under a 24 month embargo labeled 'Closed Access', the embargo will last until 2019-12-01","The student, Julio Serrano, accepted the attached license on 2017-12-04 at 14:05.","The student, Julio Serrano, submitted this Dissertation for approval on 2017-12-04 at 14:11.","This Dissertation was approved for publication on 2017-12-04 at 17:47.","DSpace SAF Submission Ingestion Package generated from Vireo submission #11833 on 2018-03-13 at 10:37:32","Made available in DSpace on 2018-03-13T17:35:46Z (GMT). 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For instance, non-Watson– Crick T–T mismatch base pairs flanked by G–C base pairs appear in myotonic dystrophy type 1 (DM1), which is caused by the expansion of CTG trinucleotide repeats (TNR) in the 3’- untranslated region of the dystrophia myotonica protein kinase (DMPK) gene. Extensive efforts have made it possible to elucidate its pathogenesis and mechanism of action. In this regard, numerous compounds have been developed that target the toxic repeating CUG RNA transcript (r(CUG)exp) and inhibit its sequestration of key pre-mRNA splicing proteins, such as MBNL1. Indeed, since we reported our first ligand JFA in 2009, our group has been at the forefront in discovering ligands that specifically bind U–U mismatches and can potentially be used as therapeutics. More recently, we have started to focus our efforts to discover molecules that target the parent CTG expanded repeats (d(CTG)exp) in hopes to develop a more promising therapeutic. A brief overview of targeting DNA, DNA mismatches, DM1 and our ligands is given in Chapter 1. A previous anisotropy screen in our lab of ligands that inhibit the MBNL1–r(CUG)exp complex identified a novel lead pyrroloquinazoline compound. However, as we will see in Chapter 2, further investigation revealed that it was selective for T–T mismatches. Interestingly, we noted that mode of binding toward CTG mismatched sites appeared to be cooperative. Due to its limited water solubility, we attempted to develop further derivatives. We took into consideration these observations to develop and improve our acridine-base ligands in the last chapter. To further improve the affinity and selectivity of our acridine-based ligands, we proceeded to develop a series of enforced stacked intercalators. Our first approach involved utilizing a larger mismatch-recognition diaminopurine unit, as the described in the first part of Chapter 3. However, although selective for T–T and C–C mismatches, its nonspecific binding was not improved. Finally, we employed a macrocyclic design, and developed a small library of macrocycles. We showed that these ligands selectively bind to CTG trinucleotide repeats in DNA with negligible nonspecific binding to duplex DNA. In addition, they were about twice as effective and selective in inhibiting transcription than the control. Lastly, we discovered that the macrocyclic structure design of our ligands did not necessarily correlate with a reduction in their cytotoxicity in HeLa cells, as we had previously hypothesized. The synthesis, biophysical studies, and in vitro activity of these macrocyclic ligands are described in the second part of Chapter 3.","Submission published under a 24 month embargo labeled 'Closed Access', the embargo will last until 2019-12-01","The student, Julio Serrano, accepted the attached license on 2017-12-04 at 14:05.","The student, Julio Serrano, submitted this Dissertation for approval on 2017-12-04 at 14:11.","This Dissertation was approved for publication on 2017-12-04 at 17:47.","DSpace SAF Submission Ingestion Package generated from Vireo submission #11833 on 2018-03-13 at 10:37:32","Made available in DSpace on 2018-03-13T17:35:46Z (GMT). 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