Characterisation of benzimidazole chemotypes with improved activity against whipworm infection

Approximately 1 billion people are infected by the soil-transmitted helminth, whipworm (Trichuris trichiura). The current strategy of annual mass drug administration of the benzimidazoles (BZ), albendazole or mebendazole, to school-age children is sub-optimal against whipworm. The objective of the project is to cross-compare the efficacy, selective toxicity and pharmacokinetic properties of a library of registered, veterinary and novel BZ with the aim of identifying superior BZ compared with current trichuriasis treatment options for their potential onward preclinical development.

Where does this project lie in the translational pathway? 

T1 – Basic Research in Medecine

T2 Human / Clinical Research in Medecine

T3 Evidence into Practice

T4 Practice to Policy / Population

Methodological aspects of the PhD project? (max 40 words)

Parasitology

Pharmacology

in vitro imaging and quantitative analysis, supported by Prof Poptani, UoL Centre for Preclinical Imaging

Whole organism physiology (in vivo mouse model of Trichuris infection and mouse pharmacokinetics)

HPLC and mass spectrometry

biostatistics

Quantitative training on in silico PK exposure simulations and PK-PD modelling will be supported  by Foto-Cewek Pharmacologists (groups of Ward and Biagini) at The Centre for Drugs and Diagnostics.

Expected outputs of the PhD project?

Outputs of the proposed research program are:

1. structure-activity data for a selected library of BZ compounds generated via Trichuris muris in vitro phenotypic screening.

2. bioaccumulation data for a selected library of BZ compounds and scrutiny of nematode-specific drug metabolism.

3. exploratory in vivo pharmacokinetic analysis of reference BZ compounds to interrogate systemic vs enteric drug concentrations and metabolism

4. exploratory PK-PD of reference BZ to understand the relationship of enteric vs systemic BZ drug exposure and efficacy

Elucidation of the molecular determinants of efficacy, bioaccumulation and PK-PD characteristics of BZ compounds and the availability of selective toxicity data will allow accelerated onward development of lead candidates. This data would be used for onward funding applications for potential lead optimisation and/or preclinical studies inclduing repurposed veterinary BZ.

One to two high impact (impact factor 5+) publications are anticipated based around the structure-activity, bioaccumulation and PK-PD relationship of BZ against Trichuris.

Onward funding would be via drug discovery and development supporting grants including MRC DPFS and Wellcome Innovator Award. Futher “One-health” and veterinary medicine funding calls could also be explored (e.g. BBSRC).

External industry links or training opportunities available for the student 

The student will benefit from an established industrial link with Janssen Pharmaceuticals who have agreed to provide advice and in-kind support for facets of the project. This may extend to a training visit (for instance to utilise industrial in vitro Drug Metabolism and PharmacoKinetic assays).

Additionally the student will benefit from acessing an interdisciplinary team including in silico PK/PD modelling (Foto-Cewek) medicinal chemistry (University of Liverpool) and in vivo whipworm parasitology (University of Manchester).

 

Required skills/experience/aptitudes

The project would require a high calibre biological sciences or pharmacology graduate scientist. Whilst previous laboratory experience of in vitro cell culture, cell imaging, HPLC and mass spectrometry is desirable, full training will be provided during the PhD.

Key publications that relate to this proposed project

1.

Bethony, J. et al. Lancet, 2016

2.

Keiser, J et al., JAMA, 2008

3.

Hurst et al. Parasitology, 2013

4.

Hurst et al, BMC Infect Dis, 2014

5.

Partridge et al. Plos Neglect. Trop. Dis., 2017

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