Industrial scale high-throughput screening delivers multiple fast acting macrofilaricides

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Clare, Rachel H, Bardelle, Catherine, Harper, Paul, Hong, W David, Borjesson, Ulf, Johnston, Kelly L, Collier, Matthew, Myhill, Laura, Cassidy, Andrew, Plant, Darren et al (show 21 more authors) , Plant, Helen, Clark, Roger, Cook, Darren AN, Steven, Andrew, Archer, John, McGillan, Paul, Charoensutthivarakul, Sitthivut, Bibby, Jaclyn, Sharma, Raman, Nixon, Gemma L, Slatko, Barton E, Cantin, Lindsey, Wu, Bo, Turner, Joseph, Ford, Louise, Rich, Kirsty, Wigglesworth, Mark, Berry, Neil G ORCID: 0000-0003-1928-0738, O'Neill, Paul M ORCID: 0000-0003-4338-0317, Taylor, Mark J and Ward, Stephen A (2019) Industrial scale high-throughput screening delivers multiple fast acting macrofilaricides. NATURE COMMUNICATIONS, 10 (1). 11-.

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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.

Item Type:	Article
Uncontrolled Keywords:	Antimicrobial therapy, Cheminformatics, High-throughput screening, Parasitic infection
Depositing User:	Symplectic Admin
Date Deposited:	11 Jan 2019 16:51
Last Modified:	19 Jan 2023 01:07
DOI:	10.1038/s41467-018-07826-2
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3031162