Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.674927
Title: Accelerating antimalarial drug discovery through repositioning
Author: Matthews, H.
Awarding Body: University of Salford
Current Institution: University of Salford
Date of Award: 2013
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Abstract:
Of the plethora of parasitic diseases that afflict mankind, malaria remains the most significant with 100-300 million cases reported annually and 600,000 fatalities. Treatment and control measures have been hampered by the emergence of drug resistance to most antimalarial therapies. Early signs of drug resistance to the current frontline option, the artemisinins, make it imperative that novel drug candidates are discovered. One possible short-term solution is drug repositioning, via screening existing FDA-approved (Food and Drug Administration agency) drug libraries for antimalarial activity. Towards this goal, two, fast, simple, and reliable in vitro SYBR Green-based drug susceptibility assays were optimised. The first, the SYBR Green microplate method offered a medium throughput option that was used to screen two FDA-approved libraries (Z score = 0.68 +0.06), LOPAC and ENZO (~700 compounds). Approximately 60 hits, defined as > 50 % inhibition at 2.5 µM, were identified by the preliminary screen. The SYBR Green flow cytometer method, capable of providing direct parasitaemia estimates and stage-specific information, was used for second-phase characterisation of the hits. From these, antiamoebic compound emetine dihydrochloride hydrate was identified as a potent inhibitor of the multidrug resistant Plasmodium falciparum, strain K1, with an IC50 of 47 nM (95 % confidence interval 44.92-49.17). Further characterisation of the compound involved analysis of the parasite killing profile, to determine the parasite reduction ratio (PRR) and parasite clearance time (PCT) as well drug interaction analysis with existing antimalarials. Emetine was shown to have a similar killing profile to atovaquone inferring a similar mitochondrial mode of action, corroborated by fluorescence staining with the JC-1 mitochondrial probe. Taken together, emetine’s pharmacokinetic matching and synergy with atovaquone provide an exciting drug combination for further investigation. The relatively high hit rate presented in the study, and in vitro workflow outlined for emetine, also showed drug repositioning to be a promising option for antimalarial drug discovery.
Supervisor: Not available Sponsor: University of Salford
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.674927  DOI: Not available
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