Industrial scale high-throughput screening delivers multiple fast acting macrofilaricides

Nature Communications - Tập 10 Số 1
Rachel H. Clare1, Catherine Bardelle2, Paul Harper2, W. David Hong3, Ulf Börjesson4, Kelly L. Johnston1, Matthew Collier2, Laura J. Myhill1, Andrew Cassidy1, Darren Plant2, Helen Plant2, Roger Clark2, Darren A. N. Cook1, Andrew Steven1, John Archer1, Paul McGillan3, Sitthivut Charoensutthivarakul1, Jaclyn Bibby3, Raman Sharma1, Gemma L. Nixon3, Barton E. Slatko5, Lindsey Cantin5, Bo Wu5, Joseph D. Turner1, Louise Ford1, Kirsty Rich2, Mark Wigglesworth2, Neil G. Berry3, Paul M. O’Neill3, Mark J. Taylor1, Stephen A. Ward1
1Centre for Drugs and Diagnostics, Department of Parasitology, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, L3 5QA, UK
2Hit Discovery, Discovery Sciences, IMED Biotech Unit, AstraZeneca, Macclesfield SK10 4TG, UK
3Department of Chemistry, University of Liverpool, Liverpool L69 7ZD, UK
4Hit Discovery, Discovery Sciences, IMED Biotech Unit, AstraZeneca, Gothenburg, SE-431 83, Sweden
5Genome Biology Division, New England Biolabs, Inc, Ipswich, 01938, MA, USA

Tóm tắt

AbstractNematodes 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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