High-throughput drug screening for Neglected Tropical Diseases: from filariasis to snakebite

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Following the publication of our academic-industrial partnership project, which delivered the largest ever high throughput screen and identified fast acting anti-Wolbachia compounds for the treatment of filarial diseases, I subsequently completed my PhD within the anti-Wolbachia consortium at the Liverpool School of Tropical Medicine (LSTM).

This consortium has resulted in the progression of two candidates to phase 1 trials. The skills that I gained working on this project, alongside the ensuing publications (10 papers as first or co-author), were crucial to me gaining my first post-doctoral position. In January 2020, I began working in the Centre for Snakebite Research & Interventions (CSRI) with Professor Nicholas Casewell on a project to identify novel drugs for community deliverable treatment for snakebite, with one exemplary piece of work recently published in Nature Communications (Albulescu et al. 2020). Snakebite causes substantial global mortality and morbidity. To put this health crisis in context, on average every five minutes 50 people are bitten by a snake, four of whom will be permanently disabled and one will die. This burden is weighted heavily towards the rural poor, predominantly in India and across Africa.

My current work involves using my prior skills to build high throughput screening capabilities, initially focused on a new academic-industry collaboration between the Centre for Snakebite Research & Interventions (CSRI) at LSTM and Johnson & Johnson. The goal here is to identify inhibitory molecules that act on one key toxin family found in snake venoms (snake venom metalloproteinases), which causes both mortality through haemotoxic effects (haemorrhage and coagulation) and morbidity due to local tissue damage.There is hope that this novel therapeutic option of community deliverable drugs, most likely in a drug cocktail against multiple venom toxins, will vastly improve patient outcomes for global snakebite victims, not only through the treatment itself but also as an affordable therapy. In comparison, current antivenom treatments cripple whole families economically, and all too often families do not seek treatment due to the unaffordability of therapy. However, to achieve this exciting novel therapeutic goal, a snakebite drug will need to overcome many hurdles, with funding being the most critical for tackling this neglected tropical disease. Continued academic-industrial partnerships, as for both my projects, and increased global advocacy to address the snakebite crisis, give hope that this will be achievable.

 References

Clare, R.H., Bardelle, C., Harper, P., Hong, W.D., Börjesson, U., Johnston, K.L., Collier, M., Myhill, L., Cassidy, A., Plant, D., Plant, H., Clark, R., Cook, D.A.N., Steven, A., Archer, J., McGillan, P., Charoensutthivarakul, S., Bibby, J., Sharma, R., Nixon, G.L., Slatko, B.E., Cantin, L., Wu, B., Turner, J., Ford, L., Rich, K., Wigglesworth, M., Berry, N.G., O’Neill, P.M., Taylor, M.J. & Ward, S.A. 2019. Industrial scale high-throughput screening delivers multiple fast acting macrofilaricides. Nature Communications, 10(1), p.11.

Albulescu, L.O., Xie, C., Ainsworth, S., Alsolaiss, J., Crittenden, E., Dawson, C.A., Softley, R., Bartlett, K. E., Harrison, R.A., Kool, J., Casewell, N.R. 2020. A therapeutic combination of two small molecule toxin inhibitors provides pancontinental preclinical efficacy against viper snakebite. Nature Communications, in press.

Links

https://nature-research-under-consideration.nature.com/posts/a-therapeutic-combination-of-two-small-molecule-toxin-inhibitors-provides-pancontinental-preclinical-efficacy-against-viper-snakebite   

https://www.lstmed.ac.uk/

https://www.lstmed.ac.uk/the-centre-for-snakebite-research-interventions

https://www.wipo.int/research/en/news/2020/news_0018.html

https://spark.adobe.com/page/2VjJdth26Yg9n/

https://spark.adobe.com/page/2VjJdth26Yg9n/

https://vimeo.com/167436988

https://www.nature.com/articles/s41467-018-07826-2

https://awol.lstmed.ac.uk/

https://www.liverpool.ac.uk/chemistry/

https://www.astrazeneca.com/

Rachel Clare

Post-doctoral Research Associate, Liverpool School of Tropical Medicine

Drug discovery, specialising in screening for Neglected Tropical Diseases through high-throughput and high content drug screening. I completed my PhD in March 2019, which identified novel antibacterials which target the endosymbiotic bacteria, Wolbachia, of the worms which cause the tropical diseases: lymphatic filariasis and onchocerciasis. I started my first PDRA in January 2020 on drug discovery for snakebite within the Centre for Snakebite Research & Interventions (CSRI) at Liverpool School of Tropical Medicine (LSTM).

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