The optimisation of transfer chemistries for DNA-templated synthesis (DTS)

Crow, Bethany (2025). The optimisation of transfer chemistries for DNA-templated synthesis (DTS). University of Birmingham. Ph.D.

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Abstract

Inspired by the ribosome, researchers have developed strategies to synthesise programmable, sequence-specific polymers for material discovery. One method aiming to achieve this is DNA-templated synthesis (DTS). DTS co-localises reactive tags attached to complementary DNA strands, initiating a chemical reaction. Sequentially, spent adapters are replaced, through DNA’s complementary base binding, to produce identifiable sequence-specific polymers. However, currently, the most successful chemistries used for monomer transfer are prone to degradation, limiting the reaction yield and polymer growth. Therefore, this thesis explores the optimisation of DTS transfer chemistries to limit the hydrolysis of reactive tags.
Chapter 1 provides a simplified introduction to ribosomal peptide synthesis and examples of how researchers have been inspired to develop similar strategies for artificial polymer synthesis, i.e. DTS. The chemistries and architectures that have demonstrated successful transfer of DTS monomers, as well as their limitations, are discussed. Susceptible to hydrolysis in aqueous conditions, Chapter 2 investigates the cause for thioester stabilisation in a DTS across-the-helix aminolysis mechanism, in order to harness its full capabilities. In addition, the effects nucleobases have on the architecture’s DTS yields and thioester protection are explored. In order to improve reaction yields and rates, Chapter 3 introduces a new DTS electrophile, the selenoester, investigating its capabilities in a single-step DTS assay. Chapter 4 attempts to optimise Chapter 3′s selenoester-mediated DTS further, as well as incorporate the electrophile into a multistep DTS system.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):