Industrial scale high-throughput screening delivers multiple fast acting macrofilaricides View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2019-12

AUTHORS

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

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. More... »

PAGES

11

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/s41467-018-07826-2

DOI

http://dx.doi.org/10.1038/s41467-018-07826-2

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1110929185

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/30602718


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