Dynamic Combinatorial Chemistry as a Tool in the Identification of Novel Receptors for Biomolecules Public Deposited

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  • March 20, 2019
Creator
  • Ingerman, Lindsey
    • Affiliation: College of Arts and Sciences, Department of Chemistry
Abstract
  • The work presented in this thesis highlights various advances in the field of dynamic combinatorial chemistry (DCC), both in the development of new types of dynamic libraries and in the investigation of molecular receptors for biomolecules of interest. DCC has emerged in recent years as a new strategy for the discovery of host-guest systems based on the generation of libraries via reversible chemistry. The true utility of DCC lies in the fact that recognition of a guest molecule causes the equilibrium to shift, allowing for amplification and detection of novel receptors. This technology has been utilized most notably for the identification of synthetic receptors for protein post-translational modifications, particularly methylated lysines and arginines. These modifications are of great interest due to their crucial role in gene expression and cell signaling. Small molecule receptors have been demonstrated via DCC that discriminate for trimethyllysine over the lower methylation states, for example, paralleling the affinity and selectivity of the native protein receptor. This suggests that such synthetic receptors have a promising future as affinity reagents for PTMs. Also of interest are methylated nucleotides, and larger peptide based macrocycles have been shown to function as selective receptors for 7-methyl guanosine via DCC, revealing the importance of the methyl group in strengthening this host-guest interaction. In addition to executing molecular recognition studies via DCC, we have expanded upon the present collection of building blocks and libraries that have been demonstrated previously. An azobenzene moiety was incorporated into a doubly dynamic library to highlight the utility of photocontrolled libraries. Through templation with a polyproline peptide the amplification of an azobenzene containing macrocycle was demonstrated. Photoresponsive receptors of this type have the potential to allow for greater control over molecular recognition events. Furthermore, new libraries of peptidic marcocycles were demonstrated via thioester exchange. This work is particularly advantageous in that it is feasible to generate large numbers of cyclic peptides efficiently within hours for further screening. The reaction dynamics and the kinetic determinants of macrocycle formation were investigated and found to be highly dependant on the peptide building block structures.
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  • In Copyright
Advisor
  • Waters, Marcey
  • Gagne, Michel
  • Lawrence, David
  • Brookhart, Maurice
  • Jorgenson, James
Degree
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill Graduate School
Graduation year
  • 2010
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