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Title: Design and synthesis of high affinity ligands for cyclophilins
Author: Dunsmore, Colin John
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2005
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An in-house in silico database mining programme (LIDAEUS) was used to screen a library of small molecules for binding to CypA. This approach identified dimedone 33 as a lead which mimics two of the key interactions of CsA and was found to possess a Kd = 22 mM (cf. 30 nM for CsA). Several rounds of chemical derivatisation led to the synthesis of conformationally constrained ligands, the best of which 123 was found to bind CypA with a Kd = 15 μM, a greater than 1000-fold improvement on the original lead. (Fig. 3828) Inhibitor 123 was tested in vivo against the nematode C. elegans to screen for antiparasitic effects. High concentrations (> 500 μM) of 123 were lethal resulting in rapid death of the worms. At lower concentrations the worms suffered growth defects and displayed cuticle shedding and severe gut development disorders, similar in phenotype to those observed in organisms treated with CsA. Fluorescent tags were incorporated to investigate the uptake and localisation of the ligand within C. elegans. Sulfonamide 168a displayed similar effects to 123 and CsA in vivo and its fluorescence was detected throughout the worms’ gut lumen in areas where cyclophilins are thought to be involved in structural formation of the gut lining. These results demonstrate the potential of such ligands to act as chemical probes for elucidating the role of cyclophilins at different stages of C. elegans development. Such a forward chemical genetics approach could, in future, provide valuable information concerning the biological mode of action of cyclophilins in nematode parasites and help to identify new targets for antiparasitic drugs.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available