Repositioning histone modifying enzyme (HME) inhibitors as next-generation flukicides

Lead Research Organisation: Aberystwyth University
Department Name: IBERS

Abstract

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Publications

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Studentship Projects

Project Reference Relationship Related To Start End Student Name
BB/T008776/1 30/09/2020 29/09/2028
2473651 Studentship BB/T008776/1 30/09/2020 29/09/2024 Sarah Davey
 
Description Discovery of three new lead compounds (potential new chemotherapies) against Fasciola hepatica by repositioning existing histone modification inhibitors (previously used in cancer research).

Prioritisation of the inhibitor GSK-J4 as a lead compound for anthelmintic development.

Development of deep-learning based parasite viability scoring models (split into segmentation and classification models) to improve objectivity of parasite scoring post drug treatment. This system will ultimately enable more high-throughput, quantifiable screening of compounds against Fasciola hepatica in the future.
Exploitation Route Additional characterisations of the molecular and phenotypic effects of hit compounds not performed in thesis due to constraints of time, resources and funding (e.g. additional enzymatic, proteomic, transcriptomic/RNA-seq, RNAi experiments).

Translational application of hit compounds to other closely related parasites (e.g. Fasciola gigantica, Calicophoron daubneyi) or distally related infectious organisms (e.g., protozoans).

Modification of existing deep learning segmentation and phenotyping frameworks to include additional phenotypes (i.e., training with images from a wider range of compounds), imaging systems, parasites and life stages (e.g., Schistosoma mansoni, adult stage parasites etc.) Possibility to extend model to characterise stage development and measure parasite growth over time.
Sectors Agriculture

Food and Drink

Digital/Communication/Information Technologies (including Software)

Pharmaceuticals and Medical Biotechnology

 
Description Spring Meeting Travel Award
Amount £200 (GBP)
Organisation British Society for Parasitology (BSP) 
Sector Charity/Non Profit
Country United Kingdom
Start 03/2022 
End 03/2022
 
Title Deep learning segmentation and phenotyping models for Fasciola hepatica NEJs 
Description Early stages development of Python-based object segmentation and classification models for drug treated Fasciola hepatica newly excysted juveniles. Designed to work with Molecular Devices microscope systems but could be adapted to encompass additional systems. Works using mask-R-CNN based segmentation techniques in TensorFlow model garden and Xception-based classification in Keras. Training and optimisation of models performed over a year using pre-trained weights from Schistosoma mansoni models produced within the Hoffmann laboratory. Part of a collaboration with Informatics Unlimited (Cambridge). Aim is to further develop these basal models into an integrated software package with a GUI that will read images directly from a SQL database in house at Aberystwyth University. 
Type Of Material Computer model/algorithm 
Year Produced 2024 
Provided To Others? No  
Impact Deployment of this model will allow quantitative parasite viability scoring based on phenotype that will reduce subjectivity of existing manual, categorical scoring system. Upscaling this model will increase reliability and accuracy of hit compound identification in F. hepatica, ultimately enabling high throughput drug screening and advancing the development of novel anthelmintics. 
 
Description IVL-11 as a flukicidal drug 
Organisation Ridgeway Research
Country United Kingdom 
Sector Private 
PI Contribution Ex vivo brightfield and fluorescence imaging (dextran, DAPI, phalloidin) of cultured Fasciola hepatica NEJs at 72 hours post compound treatment with IVL-11 (alpha hederin) and triclabendazole. Titrations of compounds for EC50 calculations in both IVL11 and TCBZ (24, 48 and 72 hours). Wet weight measurement of ex vivo fluke from animal trials using triclabendazole, closantel and IVL-11 (various concentraions) and statistical analysis of drug treatment impacts on fluke size and fecundity.
Collaborator Contribution Investigation of the pharmacokinetics and efficacy of 5 saponin groups compounds in sheep. Modification of IVL-11 formulation to improve efficacy and tolerance. In silico compound modelling. Retesting of modified IVL-11 formulation in animal trials to determine maximal tolerated dose and comparability to triclabendazole and closantel.
Impact Data pending publication (likely Phytotherapy Research). Multidisciplinary collaboration between in vitro animal scientists, compound chemists, parasitologists and computational biologists.
Start Year 2022
 
Description Department Open Days 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Undergraduate students
Results and Impact Attended campus open days for prospective students and their parents on various weekends from 2020 - 2023. Provided facility and campus tours, demonstrations of practicals and general advice to applicants.
Year(s) Of Engagement Activity 2020,2021,2022,2023
 
Description School Visit 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Delivered a careers fair stand at a secondary school to Year 8 students. Presented for parasitology as a specific career path, as well as encouraging students to pursue science more generally. The engagement involved presenting preserved parasites, allowing students to use microscopes to view fixed samples on slides, and demonstrating a prototype digital microscope built during my project.
Year(s) Of Engagement Activity 2024