{"id":{"repo_id":"uiuc","oai_identifier":"oai:www.ideals.illinois.edu:2142/115687"},"canonical_url":"https://search.dev.ndltd.org/etd/uiuc/oai:www.ideals.illinois.edu:2142/115687","repository":{"repo_id":"uiuc","name":"University of Illinois - Urbana-Champaign","base_url":"https://www.ideals.illinois.edu/oai-pmh"},"display":{"title":"Nucleic acid-templated assembly of therapeutic agents","abstract":"Submission published under a 24 month embargo labeled 'Closed Access', the embargo will last until 2024-05-01","abstract_html":"Submission published under a 24 month embargo labeled 'Closed Access', the embargo will last until 2024-05-01","abstract_has_math":false,"creators":["Krueger, Sarah Bonson"],"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","Mitchell, Douglas A","Jin, Hong","Olshansky, Lisa"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2022,"date_issued":"2022-05","date_published":"2022-05","updated_at":"2026-07-22T22:24:55Z","subjects":["nucleic acid","DM1","transcription","assembly","dynamic covalent chemistry"],"languages":["en","eng"],"rights":["Copyright 2022 Sarah Bonson Krueger"],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://hdl.handle.net/2142/115687","outbound_label":"Handle","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Zimmerman, Steven C","Mitchell, Douglas A","Jin, Hong","Olshansky, Lisa"]},{"key":"dc:creator","label":"Author","values":["Krueger, Sarah Bonson"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2022-05","2022-04-21"]},{"key":"dc:type","label":"Dc Type","values":["text","Thesis"]},{"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":["nucleic acid","DM1","transcription","assembly","dynamic covalent chemistry"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["en","eng"]},{"key":"dc:rights","label":"Dc Rights","values":["Copyright 2022 Sarah Bonson Krueger"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["https://hdl.handle.net/2142/115687"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description","label":"Description","values":["Submission published under a 24 month embargo labeled 'Closed Access', the embargo will last until 2024-05-01","The student, Sarah Krueger, accepted the attached license on 2022-04-09 at 14:19.","The student, Sarah Krueger, submitted this Dissertation for approval on 2022-04-09 at 14:34.","This Dissertation was approved for publication on 2022-04-21 at 07:49.","DSpace SAF Submission Ingestion Package generated from Vireo submission #17618 on 2022-11-11 at 12:18:58","Small molecule targeting of nucleic acids has come into focus as a therapeutic strategy for diseases such as myotonic dystrophy type 1 (DM1), a trinucleotide repeat disease characterized by its RNA gain-of-function mechanism. Methods of targeting nucleic acids range from the use of antisense oligonucleotides to the use of small molecules and oligomeric compounds to modulate symptoms. Of particular interest for targeting nucleic acid repeats is the use of multivalent targeting agents. Herein, we have explored the assembly of multivalent targeting agents using the nucleic acid target as a template for in situ synthesis. Using proximity driven azide-alkyne click, we developed a screening approach through which several hit compounds were found. As the proximity-induced click reaction is irreversible and requires long reaction times of at least 1 day before product is observed, we set out to develop a method for rapid, template-selected, reversible assembly of therapeutic agents in situ via aldehyde-amine condensation. After a proof-of-concept assay with compounds that contain two reactive aldehyde or amine groups, a library of rationally designed small molecule targeting agents containing aldehyde or amine functionality was synthesized and screened. The selective assembly of fragments on template was confirmed by MALDI-MS in the presence of DM1- and Huntington’s Disease (HD)-relevant nucleic acid sequences. Of interest for both DM1 and HD, the resulting hit combinations of aldehyde and amine inhibited the formation of toxic RNA in vitro in a cooperative manner with low micromolar IC50 values and rescued mis-splicing in DM1 model cells. This reversible template-selected assembly is a promising strategy to achieve multivalent targeting and could be utilized to develop strong and selective binders for other disease-relevant nucleic acid targets."]},{"key":"dc:format","label":"Dc Format","values":["application/pdf"]},{"key":"dc:title","label":"Title","values":["Nucleic acid-templated assembly of therapeutic agents"]}]}],"canonical_facts":{"dc:contributor":["Zimmerman, Steven C","Mitchell, Douglas A","Jin, Hong","Olshansky, Lisa"],"dc:creator":["Krueger, Sarah Bonson"],"dc:date":["2022-05","2022-04-21"],"dc:description":["Submission published under a 24 month embargo labeled 'Closed Access', the embargo will last until 2024-05-01","The student, Sarah Krueger, accepted the attached license on 2022-04-09 at 14:19.","The student, Sarah Krueger, submitted this Dissertation for approval on 2022-04-09 at 14:34.","This Dissertation was approved for publication on 2022-04-21 at 07:49.","DSpace SAF Submission Ingestion Package generated from Vireo submission #17618 on 2022-11-11 at 12:18:58","Small molecule targeting of nucleic acids has come into focus as a therapeutic strategy for diseases such as myotonic dystrophy type 1 (DM1), a trinucleotide repeat disease characterized by its RNA gain-of-function mechanism. Methods of targeting nucleic acids range from the use of antisense oligonucleotides to the use of small molecules and oligomeric compounds to modulate symptoms. Of particular interest for targeting nucleic acid repeats is the use of multivalent targeting agents. Herein, we have explored the assembly of multivalent targeting agents using the nucleic acid target as a template for in situ synthesis. Using proximity driven azide-alkyne click, we developed a screening approach through which several hit compounds were found. As the proximity-induced click reaction is irreversible and requires long reaction times of at least 1 day before product is observed, we set out to develop a method for rapid, template-selected, reversible assembly of therapeutic agents in situ via aldehyde-amine condensation. After a proof-of-concept assay with compounds that contain two reactive aldehyde or amine groups, a library of rationally designed small molecule targeting agents containing aldehyde or amine functionality was synthesized and screened. The selective assembly of fragments on template was confirmed by MALDI-MS in the presence of DM1- and Huntington’s Disease (HD)-relevant nucleic acid sequences. Of interest for both DM1 and HD, the resulting hit combinations of aldehyde and amine inhibited the formation of toxic RNA in vitro in a cooperative manner with low micromolar IC50 values and rescued mis-splicing in DM1 model cells. This reversible template-selected assembly is a promising strategy to achieve multivalent targeting and could be utilized to develop strong and selective binders for other disease-relevant nucleic acid targets."],"dc:format":["application/pdf"],"dc:identifier":["https://hdl.handle.net/2142/115687"],"dc:language":["en","eng"],"dc:rights":["Copyright 2022 Sarah Bonson Krueger"],"dc:subject":["nucleic acid","DM1","transcription","assembly","dynamic covalent chemistry"],"dc:title":["Nucleic acid-templated assembly of therapeutic agents"],"dc:type":["text","Thesis"],"thesis:degree_discipline":["Chemistry"],"thesis:degree_level":["Dissertation"],"thesis:degree_name":["Ph.D."],"thesis:institution_name":["University of Illinois at Urbana-Champaign"]},"updated_at":"2026-07-22T22:24:55Z"}