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Title: Anti-filarial drug discovery : targeting the Wolbachia endosymbiont
Author: Clare, R.
Awarding Body: University of Liverpool
Current Institution: University of Liverpool
Date of Award: 2019
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The diseases onchocerciasis and lymphatic filariasis (LF) are a leading cause of global morbidity affecting over 85.5 million people throughout the tropics. Clinical pathology for these diseases ranges from localised pain to hydrocele, lymphoedema and elephantiasis for LF and skin disease to blindness for onchocerciasis. Both filarial diseases are caused by parasitic filarial worm infections. Treatments for these diseases are limited to just three drugs (ivermectin (IVM), albendazole (ALB) and diethylcarbamazine citrate (DEC)), all of which principally kill only the larval stages (microfilaricidal) of these worms leaving adult worms able to re-populate the microfilarial (mf) reservoirs and subsequently continue the transmission cycle. Macrofilaricidal drugs which target the adult stages are urgently needed to aid elimination. The Anti-Wolbachia Consortium (A·WOL) is working on such treatments by targeting the endosymbiotic bacteria which reside within the filarial worms. Clinical field trials have provided proof of concept evidence of targeting Wolbachia with the antibiotic doxycycline. However, doxycycline requires a prolonged treatment course of 4-6 weeks and is contraindicated in pregnancy and children under 8 years old, therefore there is an urgent need for repurposed or novel drugs with a shorter treatment timeframe and utility in excluded populations. This study presents the development of a high content screen which enabled a 25-fold increase in throughput in screening capacity for the A·WOL drug discovery programme, from 1,000 to 25,000 compounds per month. This screen was instrumental in allowing the programme to initiate a medicinal chemistry 'hit to lead' and lead optimization development programme. Following this assay development, a collaboration with A·WOL and AstraZeneca allowed for a paradigm shift in the evolution of this screen to an industrial scale high-throughput assay (HTS). This validated assay was used to screen over 1.8 million compounds: 1.3 million from the AstraZeneca collection and 0.5 million from the Medicines for Malaria Venture (MMV). This HTS resulted in ~20,000 'hit' compounds with anti-Wolbachia activity. Triaging of the compounds was carried out through secondary dose response screens of ~6,000 compounds followed by further triaging through both bioinformatic assessment as well as tertiary larval (mf) testing. The resultant hit chemotypes were tested within a newly developed time kill assay validated as part of this study. This assay identified 5 novel chemotypes with faster acting anti-Wolbachia activity than the existing portfolio of A·WOL drugs and lead candidates.
Supervisor: Mark, Taylor ; Stephen, Ward ; Giancarlo, Biagini Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral