A collaboration between the Anti-Wolbachia consortium (Liverpool School of Tropical Medicine and The University of Liverpool) and AstraZeneca has paved the way to identify novel compounds with the potential for the treatment of lymphatic filariasis and onchocerciasis. Both diseases are leading causes of global disability. The A·WOL consortium over the last 10 years has been focusing on a unique drug target, Wolbachia, the endosymbiotic bacteria which live within the nematode worms causing these diseases. Through depletion of this bacteria the worm’s life span is reduced from decades to 1-2 years, as well as sterilising the adults, which blocks the transmission of the diseases by blood feeding insects (black fly and mosquitoes).

This collaboration resulted in the successful screening of 1.3 million of AstraZeneca’s compounds against Wolbachia (within a model insect cell line). This screen was based on an adaptation of the current screening protocols carried out by A·WOL at the Liverpool School of Tropical Medicine in collaboration with the chemistry department at The University of Liverpool, with the addition of utilising AstraZeneca’s state of the art high throughput facilities. This fully automated screen allowed for impressive screening timelines of just 3 months, including dose response screening of 6,000 compounds with anti-Wolbachia activity in the primary screen. This was just the beginning of the exciting outputs from this collaboration. Further screening and triaging based on the chemistry and pharmacology of the compounds, identified 5 clusters of compounds which delivered rapid anti-Wolbachia activity within just a single day. This unique killing profile could translate into radically shorter treatment regimens, which could enable the scale-up of this approach to community level programmatic delivery and dramatically shorten the time taken to meet the elimination goals of these devastating diseases.

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.

Links

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

https://www.nature.com/collections/xqqjnjxkct

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

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

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

https://www.astrazeneca.com/