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Title: Molecular recognition of damaged DNA using synthetic affinity reagents
Author: Turner, Jayne Susan
ISNI:       0000 0001 3538 7987
Awarding Body: Open University
Current Institution: Open University
Date of Award: 2004
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Potentially carcinogenic DNA damage that may be derived from dietary sources can be quantified using a number of methods. Some of the best of these methods are based on the use of antibodies that have high affinity and specificity for modified DNA bases. However, given the sometimes limited availability of antibodies there is a requirement for novel reagents that mimic the properties of the best antibodies. From a chemical perspective antibodies are 'over engineered' and synthetic affinity reagents would recreate the optimal properties of the binding site with respect to selectivity and affinity. Phage display was used to identify amino acid residues that contribute to recognition of a diet derived DNA adduct O6-carboxymethyl-2'-deoxyguanosine. However, this information was not sufficient to synthesise a novel peptide reagent directly and it was decided to develop an approach whereby a library of compounds was synthesised which includes the characteristics expected within the binding site of an antibody. This library was based around cholic acid, a readily available scaffold molecule with suitable functionality compatible with linking amino acids and a fluorescent tag. A synthetic procedure based on the formation of stable oxime derivatives of cholic acid was optimised and a small library of pyrene-tagged trisubstituted cholic acid derivatives was characterised. The library was examined for its ability to bind to affinity columns containing immobilised O6-carboxymethylguanosine and there was some evidence that indicated specific binding of a subset of library molecules.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral