Design and synthesis of dUTP nucleotidohydrolase inhibitors for use as anti-parasitic drugs.

McCarthy, Orla. 2006. Design and synthesis of dUTP nucleotidohydrolase inhibitors for use as anti-parasitic drugs. PhD Thesis, Cardiff University.

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Abstract

Parasitic protozoa cause many widespread diseases known to man such as malaria, African sleeping sickness, leishmaniasis and Chagas' disease. These diseases are particularly prevalent in the developing world and the need for new, safe and affordable drugs to treat them is urgent. Current drug treatments often result in adverse side effects and the continual emergence of resistance is extensive. The main function of nucleic acid DNA is to preserve and store genomic information in all living organisms and its integrity must be scrupulously maintained by the cell. The ubiquitous enzyme dUTP nucleotidohydrolase (dUTPase) catalyses the hydrolysis of dUTP to dUMP and can be considered as the first line of defence against incorporation of uracil into DNA. Inhibition of this enzyme results in overincorporation of uracil into DNA, leading to DNA fragmentation and cell death and is therefore lethal. By taking advantage of structural differences between the human and parasitic forms of dUTPase, selective inhibitors of the enzyme can be designed and synthesised with the aim of being developed into novel anti-parasitic drugs. Analogue based design was used to target the Plasmodium falciparum dUTPase (PfdUTPase). The structures of previously discovered selective inhibitors of the PfdUTPase were modified by insertion of an amide bond. A series of tritylated uracil acetamide derivatives were synthesised and assessed for inhibition of the enzyme and parasite growth in vitro. Unfortunately these compounds were not potent inhibitors of the PfdUTPase but do show good in vitro activity. Following the elucidation of the crystal structure of the PfdUTPase, work was focused on the improvement of known selective inhibitors of the enzyme. Structure based design methodologies were used to search for interactions within the active site and to design potentially more potent analogues in silico. The biological results are currently being awaited. Structure based design was also used to design potential lead inhibitors of the Trypanosoma cruzi dUTPase (TcdUTPase), for which no previous selective inhibitors were known. A library of uracil amino acid conjugates were synthesised by solid phase methodology. Unfortunately, the compounds did not inhibit the enzyme or parasite growth in vitro.

Item Type:	Thesis (PhD)
Status:	Unpublished
Schools:	Pharmacy
Subjects:	R Medicine > RM Therapeutics. Pharmacology
ISBN:	9781303176821
Funders:	Welsh School of Pharmacy, European Union
Date of First Compliant Deposit:	30 March 2016
Last Modified:	12 Feb 2016 23:12
URI:	https://orca.cardiff.ac.uk/id/eprint/54325

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