New001 Building research capacity for schistosomiasis drug discovery & development through high-content imaging & structural molecular biology studies
Lead Research Organisation:
London Sch of Hygiene & Tropic. Medicine
Department Name: Infectious and Tropical Diseases
Abstract
Helminth worm infections are a huge public health problem in countries with poverty and development issues where the economic impacts due to disease morbidity ultimately hamper their long-term sustainable growth. One of the main bottlenecks in the discovery of new anti-helminthic drugs is the lack of a fast, quantitative and reproductive assay method to screen and characterize the activity of candidate molecules in adult worm forms.
The research activities to be carried out are briefly described below. New and improved research capacities will be built and disseminated in Brazil, maximising their impact on the issues of poverty and economic growth.
1. The Hight Content Screen platforms (London and Rio) will identify novel small compounds active against adult schistosome worms based on a newly developed phenotypic screening strategy. The group in Rio de Janeiro is developing a novel platform for unbiased quantification of drug action against helminths that is based on automated imaging of unlabelled adult parasite worms and subsequent quantitative image analysis using custom-developed methods. A similar system based on the larval life stage of Schistosoma has been developed by the Bickle group at LSHTM (London, UK) and are able to lend technical expertise in both assay development and image analysis. Sharing ideas and experience with LSHTM would greatly accelerate the development and consolidation of the automated drug-screening platform for adult schistosomes.
2. Dr. Furnham's group at LSHTM together with the FIOCRUZ group will develop a computational method to prioritize drug targets encoded within the genomes of Schistosoma species (in particular S. mansoni) genomes and to assess if drugs currently in clinical use can be repurposed to treat schistosomiasis. Deficiency in target data prevents further development of active compounds against schistosomiasis into drugs showing higher potency, better safety and reduced propensity to develop resistance. To circumvent this limitation, phenotypes induced by compounds with unknown mechanism will be compared to the ones produced by known drugs and a statistical model will then be used to classify the compounds according to known drug mechanisms. Concurrently, drugs with known molecular targets and already used in clinical use for other diseases will be computationally evaluated to assess their suitability to be repurposed to treat schistosomiasis.
3. The Oxford Protein Production Facility has developed a range of highly specialized technologies incorporating robotic systems to enable the high throughput expression, purification and crystallization of recombinant proteins. This platform will be applied to the production of recombinant S. mansoni proteins with potential as drug targets either previously identified by our group at FIOCRUZ or selected from bioinformatics pipelines developed in [2] by Dr. Furnham's group at LSHTM.
4. S. mansoni proteins that have been produced in [3] will be screened for crystallization using the high throughput automated pipeline in the OPPF-UK. Dr. Furnham's and Dr. Silva's groups will collaborate to solve the structures of the target proteins, and then employ structure-based design methods to optimize drug binding affinities.
5. The best compounds will be selected for chemical derivatization and structural diversification to explore structure-activity relationships (SAR). Dr. Ferreira's group in UFRJ will synthesize the molecules.
6. Workshops in Brazil. Two workshops will be held at FIOCRUZ, one in each semester. The first workshop will have as its theme the high-throughput protein expression and crystallization. The second workshop will be on the Application of Computational Biology for Target Identification from Big Datasets.
The research activities to be carried out are briefly described below. New and improved research capacities will be built and disseminated in Brazil, maximising their impact on the issues of poverty and economic growth.
1. The Hight Content Screen platforms (London and Rio) will identify novel small compounds active against adult schistosome worms based on a newly developed phenotypic screening strategy. The group in Rio de Janeiro is developing a novel platform for unbiased quantification of drug action against helminths that is based on automated imaging of unlabelled adult parasite worms and subsequent quantitative image analysis using custom-developed methods. A similar system based on the larval life stage of Schistosoma has been developed by the Bickle group at LSHTM (London, UK) and are able to lend technical expertise in both assay development and image analysis. Sharing ideas and experience with LSHTM would greatly accelerate the development and consolidation of the automated drug-screening platform for adult schistosomes.
2. Dr. Furnham's group at LSHTM together with the FIOCRUZ group will develop a computational method to prioritize drug targets encoded within the genomes of Schistosoma species (in particular S. mansoni) genomes and to assess if drugs currently in clinical use can be repurposed to treat schistosomiasis. Deficiency in target data prevents further development of active compounds against schistosomiasis into drugs showing higher potency, better safety and reduced propensity to develop resistance. To circumvent this limitation, phenotypes induced by compounds with unknown mechanism will be compared to the ones produced by known drugs and a statistical model will then be used to classify the compounds according to known drug mechanisms. Concurrently, drugs with known molecular targets and already used in clinical use for other diseases will be computationally evaluated to assess their suitability to be repurposed to treat schistosomiasis.
3. The Oxford Protein Production Facility has developed a range of highly specialized technologies incorporating robotic systems to enable the high throughput expression, purification and crystallization of recombinant proteins. This platform will be applied to the production of recombinant S. mansoni proteins with potential as drug targets either previously identified by our group at FIOCRUZ or selected from bioinformatics pipelines developed in [2] by Dr. Furnham's group at LSHTM.
4. S. mansoni proteins that have been produced in [3] will be screened for crystallization using the high throughput automated pipeline in the OPPF-UK. Dr. Furnham's and Dr. Silva's groups will collaborate to solve the structures of the target proteins, and then employ structure-based design methods to optimize drug binding affinities.
5. The best compounds will be selected for chemical derivatization and structural diversification to explore structure-activity relationships (SAR). Dr. Ferreira's group in UFRJ will synthesize the molecules.
6. Workshops in Brazil. Two workshops will be held at FIOCRUZ, one in each semester. The first workshop will have as its theme the high-throughput protein expression and crystallization. The second workshop will be on the Application of Computational Biology for Target Identification from Big Datasets.
Technical Summary
The research activities to be carried out are briefly described below. New and improved research capacities will be built and disseminated in Brazil, maximising their impact on the issues of poverty and economic growth.
1. The High-Content Imaging platforms (London and Rio) will identify novel small compounds active against adult schistosome worms based on a newly developed phenotypic screening strategy.
2. Dr. Furnham's group at LSHTM together with the FIOCRUZ group will develop a computational method to prioritize drug targets within the S. mansoni genome and to assess if drugs currently in clinical use can be repurposed to treat schistosomiasis.
3. Oxford Protein Production Facility-UK (OPPF-UK) has developed a range of highly specialized technologies incorporating robotic systems to enable the high throughput expression, purification and crystallization of recombinant proteins. This platform will be applied to the production of recombinant S. mansoni proteins with potential as drug targets either previously identified by our group at FIOCRUZ or selected from bioinformatics pipelines developed in [2] by Dr. Furnham's group at LSHTM.
4. Recombinant S. mansoni proteins that have been produced in [3] will be screened for crystallization using the high throughput automated pipeline in the OPPF-UK.
5. The best compounds will be selected for chemical derivatization and structural diversification to explore structure-activity relationships (SAR).
6. Two workshops will be held at FIOCRUZ, one in each semester. The first workshop will have as its theme the high-throughput protein expression and crystallization and will be coordinated by Dr. Owens. The second workshop will be on the Application of Computational Biology for Target Identification from Big Datasets and will be coordinated by Dr. Furnham.
1. The High-Content Imaging platforms (London and Rio) will identify novel small compounds active against adult schistosome worms based on a newly developed phenotypic screening strategy.
2. Dr. Furnham's group at LSHTM together with the FIOCRUZ group will develop a computational method to prioritize drug targets within the S. mansoni genome and to assess if drugs currently in clinical use can be repurposed to treat schistosomiasis.
3. Oxford Protein Production Facility-UK (OPPF-UK) has developed a range of highly specialized technologies incorporating robotic systems to enable the high throughput expression, purification and crystallization of recombinant proteins. This platform will be applied to the production of recombinant S. mansoni proteins with potential as drug targets either previously identified by our group at FIOCRUZ or selected from bioinformatics pipelines developed in [2] by Dr. Furnham's group at LSHTM.
4. Recombinant S. mansoni proteins that have been produced in [3] will be screened for crystallization using the high throughput automated pipeline in the OPPF-UK.
5. The best compounds will be selected for chemical derivatization and structural diversification to explore structure-activity relationships (SAR).
6. Two workshops will be held at FIOCRUZ, one in each semester. The first workshop will have as its theme the high-throughput protein expression and crystallization and will be coordinated by Dr. Owens. The second workshop will be on the Application of Computational Biology for Target Identification from Big Datasets and will be coordinated by Dr. Furnham.
Planned Impact
N/A
Organisations
- London Sch of Hygiene & Tropic. Medicine (Lead Research Organisation)
- Oswaldo Cruz Foundation (Fiocruz) (Collaboration)
- Research Complex at Harwell (Collaboration)
- Federal University of Goiás (Collaboration)
- Federal University of Rio de Janeiro (Project Partner)
- Oswaldo Cruz Institute (Project Partner)
Publications

Borba JVB
(2019)
Unveiling the Kinomes of Leishmania infantum and L. braziliensis Empowers the Discovery of New Kinase Targets and Antileishmanial Compounds.
in Computational and structural biotechnology journal

Borba JVVB
(2021)
Chemogenomics and bioinformatics approaches for prioritizing kinases as drug targets for neglected tropical diseases.
in Advances in protein chemistry and structural biology

De Souza Neto LR
(2020)
In silico Strategies to Support Fragment-to-Lead Optimization in Drug Discovery.
in Frontiers in chemistry

De Souza Neto LR
(2024)
Fragment library screening by X-ray crystallography and binding site analysis on thioredoxin glutathione reductase of Schistosoma mansoni.
in Scientific reports

Giuliani S
(2018)
Computationally-guided drug repurposing enables the discovery of kinase targets and inhibitors as new schistosomicidal agents.
in PLoS computational biology

Melo-Filho CC
(2016)
QSAR-Driven Discovery of Novel Chemical Scaffolds Active against Schistosoma mansoni.
in Journal of chemical information and modeling

Moreira-Filho JT
(2021)
Schistosomiasis Drug Discovery in the Era of Automation and Artificial Intelligence.
in Frontiers in immunology

Neves BJ
(2016)
Discovery of New Anti-Schistosomal Hits by Integration of QSAR-Based Virtual Screening and High Content Screening.
in Journal of medicinal chemistry

Portelli S
(2018)
Understanding molecular consequences of putative drug resistant mutations in Mycobacterium tuberculosis.
in Scientific reports

Silva-Jr FP
(2022)
Editorial: Current approaches in infectious disease drug discovery.
in Frontiers in chemistry
Description | This award established a new collaborative partnership between three research groups in the UK and two research groups in Brazil. The aim of our collaboration was to begin the development of the next generation of drugs against Schistosomiasis, a neglected tropical disease endemic in Brazil. The award allowed us to use a newly implemented technology platform at the UK's Diamond Light Source for high throughput structure based fragment screening against a potential drug target from Schistosoma mansoni one of the major Schistosoma species the causes Schistosomiasis. We were able to screen a library of ~800 specially selected fragments derived from drug-like molecules. Using X-ray crystallography we identified a number of hits and these have been progressed and expanded to generate more drug-like molecules which are being progressed further. Researchers from Brazil were able to come to the UK labs and learn new techniques and specialist skills in protein production and screening technologies facilitating knowledge transfer and increasing research capacity in Brazil. The project was shortlisted for the 2018 Newton Prize. |
Exploitation Route | The lead hits are being taken forward in the drug discovery pathway to develop the next generation of anti-Schistosomiasis therapeutics. |
Sectors | Healthcare Pharmaceuticals and Medical Biotechnology |
Description | Schistosomiasis is one of the most prevalent helminth infections, affecting 200 million people and threatening over 800 million in 54 endemic countries, including Brazil. There is a single drug available to treat this disease, but it has limitations and is at high risk of resistance development by the parasites. Schistosomiasis is neglected by the pharmaceutical industry, with the efforts that are being made having little reported success. Yet it is still an important disease that continues to impact the poorest and most vulnerable individuals in society. This collaborative project has begun the development of the next generation of anti-Schistosoma drugs. The development of new drug interventions will effectively contribute to lowering the disease burden in Brazil, improving the the economic well-being and welfare of infected individuals. |
First Year Of Impact | 2019 |
Sector | Healthcare,Pharmaceuticals and Medical Biotechnology |
Description | Bloomsbury SET Innovation & Translation pilot scheme |
Amount | £102,000 (GBP) |
Funding ID | 4NF-LSHTM |
Organisation | United Kingdom Research and Innovation |
Department | Research England |
Sector | Public |
Country | United Kingdom |
Start | 11/2021 |
End | 05/2022 |
Description | Improving The Longevity Of New Infectious Disease Therapeutics Using Machine Learning / Artificial Intelligence In Early Stage Drug Discovery |
Amount | £488,742 (GBP) |
Funding ID | MR/T000171/1 |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 11/2019 |
End | 10/2022 |
Description | Newton Advanced Fellowship |
Amount | £75,000 (GBP) |
Organisation | Academy of Medical Sciences (AMS) |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 11/2018 |
End | 10/2020 |
Description | Wellcome Trust iTPA Translational Accelerator Award |
Amount | £10,000 (GBP) |
Organisation | Wellcome Trust |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 03/2021 |
End | 12/2021 |
Description | Fiocruz |
Organisation | Oswaldo Cruz Foundation (Fiocruz) |
Country | Brazil |
Sector | Public |
PI Contribution | We have collaborated on the prediction of molecular targets for new drugs to flight Schistosomiasis. In addition we have run a 3 day workshop on methods for drug discovery at Fiocruz. In addition members of the lab have visited Silva group to help facilitate the technology transfer of the LSHTM high content screening platform for Schistosoma. |
Collaborator Contribution | Several members of the Silva group have visited LSTHM and OPPF, this have aided the technology transfer of the high content screening platform to be established at Fiocruz, but has also provided assistance in screening compounds based on the computational prediction of molecular targets for drugs that have a potential to be repurposed as anti-schistsomal. The visits to OPPF have also aided in the protein expression, purification and crystallisation of these targets. |
Impact | This is a multi-disaplinary partnership bringing together computational biology, molecular biology and parasite biology. |
Start Year | 2015 |
Description | LabMol |
Organisation | Federal University of Goiás |
Country | Brazil |
Sector | Academic/University |
PI Contribution | I hosted a PhD student from the lab for 1 year. The student contributed to our work on Schistosomiasis drug discovery. |
Collaborator Contribution | The collaboration provided expertise in computational chemistry as well as providing support within both the wet and computational labs. |
Impact | We have co-authored a number of papers describing the results and methods of our work. |
Start Year | 2018 |
Description | OPPF |
Organisation | Research Complex at Harwell |
Department | Oxford Protein Production Facility-UK (OPPF-UK) |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | We have predicted the molecular targets in Schistosoma mansoni that could be the basis of repurposing existing FDA approved drugs. The efficacy of the drugs that could be repurposed has been verified by phenotypic screening against all three life stages, carried out in collaboration with the Bickle group at LSTHM and the Sivla group at Fiocruz Institute. Based on this we were able to provide genomic sequences of the potential targets. |
Collaborator Contribution | They have provide the equipment and resources, and as part of the collaboration with the Silva group, man power to express, purify and crystallise the gene products. |
Impact | This is a multi-disapplinary collaboration bring together computational, molecular biology, crystallography and parasite biology. |
Start Year | 2015 |
Description | EMBO Short Course - High-throughput protein production and crystallization |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | Taught on an EMBO run short course - High-throughput proteinproduction and crystallization - at Diamond Light Source, Oxford. The residential course of 25 participants proved successful and the participants engaged with the material asking questions and engaging in discussion. |
Year(s) Of Engagement Activity | 2017 |
Description | Fiocruz Workshop |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | A workshop on methods for high-throughput protein expression and crystallization as well as application of computational biology for target identification for neglected tropical disease drug discovery delivered to 70 researchers at Fiocruz Institute, Rio de Janeiro, Brazil. |
Year(s) Of Engagement Activity | 2015 |
Description | Fiocruz Workshop 2 |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | A workshop attended by 70 researchers at Fiocruz Institute, Rio de Janeiro, Brazil on high content and high through screening technology used for phenotypic screening as part of a drug discovery process. |
Year(s) Of Engagement Activity | 2015 |
Description | KCL Randall Institute Departmental lecture |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Postgraduate students |
Results and Impact | The talk generated a number of questions and further discussions afterwards. |
Year(s) Of Engagement Activity | 2016 |