The overarching theme of this thesis is the development of non-natural oligomers for use in biological applications. Chapter I details the synthesis and studies of modified peptide nucleic acid (PNA) oligomers. PNA is a synthetic oligonucleotide mimic that binds to natural nucleic acids with extremely high affinity and specificity, making them important molecules for therapeutic and diagnostic applications. We hypothesized that the incorporation of an (S,S)-trans-cyclopentyl (tcyp) ring into the backbone would pre-organize PNA oligomers for DNA binding, thus improving binding affinity. The synthesis and biophysical characterization is described, showing that tcypPNA has both improved affinity and sequence specificity for nucleic acid targets as compared to unmodified PNA. Chapter II describes the use of the improved tcypPNA in a DNA detection assay, a critical diagnostic marker for pathogens and disease state. The work described builds on the scanometric DNA detection assay, a highly-sensitive assay that exploits the unique properties of gold nanoparticles to detect the presence of extremely small quantities of DNA. We show that the use of tcypPNA as a capture strand for a synthetic target sequence leads to an improvement in sensitivity of three orders of magnitude over published results. The third chapter diverges from PNA, and describes a new class of polyamines (PAAs) designed from first principles to bind specifically to folded RNA targets. The synthesis of PAA monomers via a reductive amination strategy and their subsequent iteration into a small library of polyamines is described. A new quantum dot-based screen was developed to identify RNA binders within the library. The strategy yielded a ligand with low micromolar binding affinity for TAR RNA, as confirmed by RNA footprinting assays and NMR titrations. The fourth and final chapter explores the development of novel peptoid structures that are controlled by conformational constraint. Peptoids are peptide mimics that are well known for their ability to fold into helical conformations. Chapter IV describes the concise synthesis of a 1,5-substituted triazolyl amino acid and its incorporation into peptoid oligomers. A peptoid with a novel fold in aqueous solution was identified and a high-resolution NMR structure was solved. The result showed a peptoid that folded into a compact turn structure, effectively extending the repertoire of structural attributes available to the peptoid community.

Last modified

• 08/13/2018

Creator

• Jonathan K Pokorski

DOI

• https://doi.org/10.21985/N2J42M

Subject

• Chemistry

Keyword

• Chemistry
• Organic

Date created

• 2007-07-30

Resource type

• Dissertation

Rights statement

• In Copyright