Industrial scale high-throughput screening delivers multiple fast acting macrofilaricides

Rachel H. Clare; Catherine Bardelle; Paul Harper; W. David Hong; Ulf Börjesson; Kelly L. Johnston; Matthew Collier; Laura Myhill; Andrew Cassidy; Darren Plant; Helen Plant; Roger Clark; Darren A.N. Cook; Andrew Steven; John Archer; Paul McGillan; Sitthivut Charoensutthivarakul; Jaclyn Bibby; Raman Sharma; Gemma L. Nixon; Barton E. Slatko; Lindsey Cantin; Bo Wu; Joseph Turner; Louise Ford; Kirsty Rich; Mark Wigglesworth; Neil G. Berry; Paul M. O’Neill; Mark J. Taylor; Stephen A. Ward

doi:10.1038/s41467-018-07826-2

Industrial scale high-throughput screening delivers multiple fast acting macrofilaricides

Rachel H. Clare, Catherine Bardelle, Paul Harper, W. David Hong, Ulf Börjesson, Kelly L. Johnston, Matthew Collier, Laura Myhill, Andrew Cassidy, Darren Plant, Helen Plant, Roger Clark, Darren A.N. Cook, Andrew Steven, John Archer, Paul McGillan, Sitthivut Charoensutthivarakul, Jaclyn Bibby, Raman Sharma, Gemma L. NixonBarton E. Slatko, Lindsey Cantin, Bo Wu, Joseph Turner, Louise Ford, Kirsty Rich, Mark Wigglesworth, Neil G. Berry, Paul M. O’Neill, Mark J. Taylor, Stephen A. Ward^*

^*Corresponding author for this work

Biology

Research output: Contribution to journal › Article (journal) › peer-review

48 Citations (Scopus)

Abstract

Nematodes causing lymphatic filariasis and onchocerciasis rely on their bacterial endosymbiont, Wolbachia, for survival and fecundity, making Wolbachia a promising therapeutic target. Here we perform a high-throughput screen of AstraZeneca’s 1.3 million in-house compound library and identify 5 novel chemotypes with faster in vitro kill rates (<2 days) than existing anti-Wolbachia drugs that cure onchocerciasis and lymphatic filariasis. This industrial scale anthelmintic neglected tropical disease (NTD) screening campaign is the result of a partnership between the Anti-Wolbachia consortium (A∙WOL) and AstraZeneca. The campaign was informed throughout by rational prioritisation and triage of compounds using cheminformatics to balance chemical diversity and drug like properties reducing the chance of attrition from the outset. Ongoing development of these multiple chemotypes, all with superior time-kill kinetics than registered antibiotics with anti-Wolbachia activity, has the potential to improve upon the current therapeutic options and deliver improved, safer and more selective macrofilaricidal drugs.

Original language	English
Article number	11
Journal	Nature Communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-07826-2
Publication status	Published - 1 Dec 2019

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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., ... Ward, S. A. (2019). Industrial scale high-throughput screening delivers multiple fast acting macrofilaricides. Nature Communications, 10(1), Article 11. https://doi.org/10.1038/s41467-018-07826-2

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title = "Industrial scale high-throughput screening delivers multiple fast acting macrofilaricides",

abstract = "Nematodes causing lymphatic filariasis and onchocerciasis rely on their bacterial endosymbiont, Wolbachia, for survival and fecundity, making Wolbachia a promising therapeutic target. Here we perform a high-throughput screen of AstraZeneca{\textquoteright}s 1.3 million in-house compound library and identify 5 novel chemotypes with faster in vitro kill rates (<2 days) than existing anti-Wolbachia drugs that cure onchocerciasis and lymphatic filariasis. This industrial scale anthelmintic neglected tropical disease (NTD) screening campaign is the result of a partnership between the Anti-Wolbachia consortium (A∙WOL) and AstraZeneca. The campaign was informed throughout by rational prioritisation and triage of compounds using cheminformatics to balance chemical diversity and drug like properties reducing the chance of attrition from the outset. Ongoing development of these multiple chemotypes, all with superior time-kill kinetics than registered antibiotics with anti-Wolbachia activity, has the potential to improve upon the current therapeutic options and deliver improved, safer and more selective macrofilaricidal drugs.",

author = "Clare, \{Rachel H.\} and Catherine Bardelle and Paul Harper and Hong, \{W. David\} and Ulf B{\"o}rjesson and Johnston, \{Kelly L.\} and Matthew Collier and Laura Myhill and Andrew Cassidy and Darren Plant and Helen Plant and Roger Clark and Cook, \{Darren A.N.\} and Andrew Steven and John Archer and Paul McGillan and Sitthivut Charoensutthivarakul and Jaclyn Bibby and Raman Sharma and Nixon, \{Gemma L.\} and Slatko, \{Barton E.\} and Lindsey Cantin and Bo Wu and Joseph Turner and Louise Ford and Kirsty Rich and Mark Wigglesworth and Berry, \{Neil G.\} and O{\textquoteright}Neill, \{Paul M.\} and Taylor, \{Mark J.\} and Ward, \{Stephen A.\}",

note = "Publisher Copyright: {\textcopyright} 2019, The Author(s).",

year = "2019",

month = dec,

day = "1",

doi = "10.1038/s41467-018-07826-2",

language = "English",

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Clare, RH, Bardelle, C, Harper, P, Hong, WD, Börjesson, U, Johnston, KL, Collier, M, Myhill, L, Cassidy, A, Plant, D, Plant, H, Clark, R, Cook, DAN, Steven, A, Archer, J, McGillan, P, Charoensutthivarakul, S, Bibby, J, Sharma, R, Nixon, GL, Slatko, BE, Cantin, L, Wu, B, Turner, J, Ford, L, Rich, K, Wigglesworth, M, Berry, NG, O’Neill, PM, Taylor, MJ & Ward, SA 2019, 'Industrial scale high-throughput screening delivers multiple fast acting macrofilaricides', Nature Communications, vol. 10, no. 1, 11. https://doi.org/10.1038/s41467-018-07826-2

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T1 - Industrial scale high-throughput screening delivers multiple fast acting macrofilaricides

AU - Clare, Rachel H.

AU - Bardelle, Catherine

AU - Harper, Paul

AU - Hong, W. David

AU - Börjesson, Ulf

AU - Johnston, Kelly L.

AU - Collier, Matthew

AU - Myhill, Laura

AU - Cassidy, Andrew

AU - Plant, Darren

AU - Plant, Helen

AU - Clark, Roger

AU - Cook, Darren A.N.

AU - Steven, Andrew

AU - Archer, John

AU - McGillan, Paul

AU - Charoensutthivarakul, Sitthivut

AU - Bibby, Jaclyn

AU - Sharma, Raman

AU - Nixon, Gemma L.

AU - Slatko, Barton E.

AU - Cantin, Lindsey

AU - Wu, Bo

AU - Turner, Joseph

AU - Ford, Louise

AU - Rich, Kirsty

AU - Wigglesworth, Mark

AU - Berry, Neil G.

AU - O’Neill, Paul M.

AU - Taylor, Mark J.

AU - Ward, Stephen A.

PY - 2019/12/1

Y1 - 2019/12/1

N2 - Nematodes causing lymphatic filariasis and onchocerciasis rely on their bacterial endosymbiont, Wolbachia, for survival and fecundity, making Wolbachia a promising therapeutic target. Here we perform a high-throughput screen of AstraZeneca’s 1.3 million in-house compound library and identify 5 novel chemotypes with faster in vitro kill rates (<2 days) than existing anti-Wolbachia drugs that cure onchocerciasis and lymphatic filariasis. This industrial scale anthelmintic neglected tropical disease (NTD) screening campaign is the result of a partnership between the Anti-Wolbachia consortium (A∙WOL) and AstraZeneca. The campaign was informed throughout by rational prioritisation and triage of compounds using cheminformatics to balance chemical diversity and drug like properties reducing the chance of attrition from the outset. Ongoing development of these multiple chemotypes, all with superior time-kill kinetics than registered antibiotics with anti-Wolbachia activity, has the potential to improve upon the current therapeutic options and deliver improved, safer and more selective macrofilaricidal drugs.

AB - Nematodes causing lymphatic filariasis and onchocerciasis rely on their bacterial endosymbiont, Wolbachia, for survival and fecundity, making Wolbachia a promising therapeutic target. Here we perform a high-throughput screen of AstraZeneca’s 1.3 million in-house compound library and identify 5 novel chemotypes with faster in vitro kill rates (<2 days) than existing anti-Wolbachia drugs that cure onchocerciasis and lymphatic filariasis. This industrial scale anthelmintic neglected tropical disease (NTD) screening campaign is the result of a partnership between the Anti-Wolbachia consortium (A∙WOL) and AstraZeneca. The campaign was informed throughout by rational prioritisation and triage of compounds using cheminformatics to balance chemical diversity and drug like properties reducing the chance of attrition from the outset. Ongoing development of these multiple chemotypes, all with superior time-kill kinetics than registered antibiotics with anti-Wolbachia activity, has the potential to improve upon the current therapeutic options and deliver improved, safer and more selective macrofilaricidal drugs.

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Industrial scale high-throughput screening delivers multiple fast acting macrofilaricides

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