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Title: The use of monoclonal antibodies for glycoside hydrolysis
Author: Chia, T. W.-H.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 1993
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Since 1986, a wide range of reactions have been catalysed by monoclonal antibodies, many with good rate enhancements, high regio- and stereo-selectivities and high substrate specificities. As antibodies can be elicited against practically any molecule of interest, this new class of antibody molecules, commonly known as abzymes, offers a unique way of generating tailor-made, enzyme-like catalysts. We propose to investigate the possibility of using monoclonal antibodies to catalyse the hydrolysis of glycosides. Glycosides are important components of many biological processes especially in glycoproteins which make up the cell walls of bacteria and the outer coats of viruses. Catalytic antibodies raised may serve as therapeutic agents to selectively hydrolyse such carbohydrate coats. In addition, they can be used to probe the mechanisms of glycoside hydrolysis. In our initial attempts, we synthesised nojirimycin-like transition state analogues (these compounds have an extra methylene group at the C2 position) which when protonated, copies a similar charge in the transition state. Although we were successful in synthesising the benzyl-protected compound and incorporating the uv-detectable nitrophenyl molecule at C2 (to mimic the transition state of analogous nitrophenyl glucosides), the deprotection step, unfortunately, removed the nitrophenyl group too. We next attempted to synthesise an amidine analogue which would mimic both the charge and conformation of the transition state. However, the synthesis of the key intermediate, D-gluconolactam, was unsuccessful. Another chemical was then synthesised. Hydroximo-lactones are good inhibitors of β-glucosidases and could also serve as transition state analogues. Incorporation of the dinitrophenyl group followed by deprotection of the acetyl-protecting groups provided the desired product without affecting the uv-group. Attempts to attach a linker molecule (this is to minimise the response directed to the protein when raising monoclonal antibodies) directly to this hapten were unsuccessful and the linker was ultimately introduced in a protected form although this esterification step was not regioselective. Deprotection of the tert-butyl group of one isomer provided the hapten.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available