Nucleic acid-templated assembly of therapeutic agents

Krueger, Sarah Bonson

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https://hdl.handle.net/2142/115687 Copy

Description

Title

Nucleic acid-templated assembly of therapeutic agents

Author(s)

Krueger, Sarah Bonson

Issue Date

2022-04-21

Director of Research (if dissertation) or Advisor (if thesis)

Zimmerman, Steven C

Doctoral Committee Chair(s)

Zimmerman, Steven C

Committee Member(s)

• Mitchell, Douglas A
• Jin, Hong
• Olshansky, Lisa

Department of Study

Chemistry

Discipline

Chemistry

Degree Granting Institution

University of Illinois at Urbana-Champaign

Degree Name

Ph.D.

Degree Level

Dissertation

Keyword(s)

nucleic acid, DM1, transcription, assembly, dynamic covalent chemistry

Abstract

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.

Graduation Semester

2022-05

Type of Resource

Thesis

Copyright and License Information

Copyright 2022 Sarah Bonson Krueger

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