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.

Details

Title
Industrial scale high-throughput screening delivers multiple fast acting macrofilaricides
Author
Clare, Rachel H 1   VIAFID ORCID Logo  ; Bardelle, Catherine 2 ; Harper, Paul 2 ; Hong, W David 3 ; Börjesson, Ulf 4 ; Johnston, Kelly L 1 ; Collier, Matthew 2 ; Myhill, Laura 1 ; Cassidy, Andrew 1 ; Plant, Darren 2 ; Plant, Helen 2 ; Clark, Roger 2 ; Cook, Darren A N 1 ; Andrew, Steven 1 ; Archer, John 1 ; McGillan, Paul 3   VIAFID ORCID Logo  ; Charoensutthivarakul, Sitthivut 1   VIAFID ORCID Logo  ; Bibby, Jaclyn 3 ; Sharma, Raman 1 ; Nixon, Gemma L 3 ; Slatko, Barton E 5 ; Cantin, Lindsey 5 ; Wu, Bo 5 ; Turner, Joseph 1   VIAFID ORCID Logo  ; Ford, Louise 1   VIAFID ORCID Logo  ; Rich, Kirsty 2 ; Wigglesworth, Mark 2 ; Berry, Neil G 3   VIAFID ORCID Logo  ; Paul M O’Neill 3 ; Taylor, Mark J 1 ; Ward, Stephen A 1 

 Centre for Drugs and Diagnostics, Department of Parasitology, Liverpool School of Tropical Medicine, Liverpool, UK 
 Hit Discovery, Discovery Sciences, IMED Biotech Unit, AstraZeneca, Macclesfield, UK 
 Department of Chemistry, University of Liverpool, Liverpool, UK 
 Hit Discovery, Discovery Sciences, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden 
 Genome Biology Division, New England Biolabs, Inc, Ipswich, MA, USA 
Pages
1-8
Publication year
2019
Publication date
Jan 2019
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2162764164
Copyright
© 2019. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.