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Design, synthesis and evaluation of small molecules that recognize RNA
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Design, synthesis and evaluation of small molecules that recognize RNA
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Dissertation
Design, synthesis and evaluation of small molecules that recognize RNA
1997
Overview
Targeting specific RNA sequences with small molecules has promising applications for the development of cell permeable probes that can selectively interfere with RNA function and could lead to novel therapeutics acting at sites of RNA protein interactions or interferine with catalytic events involving RNA. Aminoglycoside antibiotics provide the largest class of lead structures found in nature to develop such RNA binders. They target a variety of sites within the ribosomal RNA of bacteria and interfere with the catalytic function of the ribosome. To gain insight into the RNA recognition properties of aminoglycosides, the interaction with one of their natural targets, the ribosomal A-site decoding region, has been studied with a series of model RNA hairpins. A new analytical method to measure small molecule-RNA binding based on surface plasmon resonance (SPR) was developed for these studies. It was found that in particular neomycin B and related aminoglycosides bind the A-site model RNA with high specificity and nanomolar affinity. This contrasts with the lack of specificity observed for the interaction of neomycin B with another putative RNA target, the Rev Responsive Element (RRE). The structures of naturally occurring aminoglycosides were examined in search of general RNA recognition motifs. This led to the identification of hydroxyamines as a new recognition motif for phosphodiesters and the Hoogsteen face of guanosine. Model studies in DMSO showed that the 1,3-hydroxyamine motif is particularly suitable for the strong complexation of phosphodiesters. Using this motif as a core structure, a parallel solution phase approach was developed for the construction of combinatorial libraries of small molecules that target RNA.
Publisher
ProQuest Dissertations & Theses
Subject
ISBN
9780591826098, 0591826097
