Title page for ETD etd-03252012-172449


Type of Document Dissertation
Author Bryson, David Irby
URN etd-03252012-172449
Title Targeting RNA Structures with Multivalent Branched Peptide Libraries
Degree PhD
Department Chemistry
Advisory Committee
Advisor Name Title
Santos, Webster L. Committee Chair
Carlier, Paul R. Committee Member
Etzkorn, Felicia A. Committee Member
Tanko, James M. Committee Member
Keywords
  • High Throughput Screening
  • Combinatorial Libraries
  • Branched Peptides
  • Multivalency
  • Cell Permeable Peptides
  • and Boron
  • RNA
  • HIV-1
  • Medium-Sized Ligands
Date of Defense 2012-03-19
Availability unrestricted
Abstract
RNA is essential for the transfer of genetic information, as the central dogma of biology dictates. The role of RNA, however, is not limited to serving as an information shuttle between DNA and fully functional protein. Indeed, RNA has experienced a surge of interest in the field of chemical biology for its other critical roles in biology including those in control of transcription, translation, splicing, genetic replication, and catalysis. RNA has proven to be a difficult and complex target for the design of small molecular ligands because of its structural heterogeneity and conformational flexibility. Yet, the highly folded tertiary structures of these oligomers present unique scaffolds which designed ligands should be able to selectively target. To that end, two branched peptide libraries ranging in size from 4,096–46,656 unique sequences were screened for their ability to bind HIV-1 related RNA structures, the transactivation response element (TAR) and the Rev response element (RRE). In addition to discovering a mid-nanomolar branched peptide ligand for TAR, the first branched boronic acid peptide library designed to target RNA was screened for binding to RRE. Each of these efforts resulted in the identification of selective binders to their respective RNA targets, and the unnatural branching of these compounds was demonstrated to provide a multivalent binding interaction with the RNA. Furthermore, these compounds were shown to be cell permeable and displayed little to no cytotoxicity in HeLa and A2780 cells.
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