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Title: Efforts towards the total synthesis of labelled CCL2 proteins and dipeptide chemotaxis inhibitors
Author: Hudson, Alexander Stephen
ISNI:       0000 0004 5921 4847
Awarding Body: Durham University
Current Institution: Durham University
Date of Award: 2015
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Chemokines such as CCL2 are small proteins with molecular weights between 8-10 kDa. They promote chemotaxis and play a vital role in the recruitment of leukocytes to the site of inflammation. Given their key biological functions, understanding their mechanism of action and inhibiting their action has therapeutic potential in a range of diseases. Selective inhibitors of CCL2 induced chemotaxis based on the diketopiperazine (DKP) natural product, cyclo(13,15-dichloro-L-Pro-L-Tyr) were recently reported by the Cobb group. In order to develop this work further and to produce an expanded library, we optimised an on-resin DKP synthesis. In collaboration with researchers at Newcastle Medical School, chemotaxis assays were performed in an attempted to define the structural features (required for inhibition) of the DKPs. To faciliate the aforementioned work, facile synthetic routes to a number of novel heteraromatic and proline derivatives were developed. The posttranslational nitration of CCL2 is used as a mechanism to a modulate CCL2. However, in all previous studies nitrated CCL2 was utilised as a heterogeneous mix of protein. Having access to single site nitrated CCL2 will enable the mechanism of abrogration to be pinpointed to a specific residue. Therefore, the total chemical synthesis of both native CCL2 and site-specifically nitrated CCL2 via solid phase peptide synthesis (SPPS) was undertaken. The work focused on the potential application of microwave assisted SPPS as a means to rapidly access the target proteins.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available