Journal Article

Industrial scale high-throughput screening delivers multiple fast acting macrofilaricides

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

2019

Overview

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. Parasitic nematodes causing onchocerciasis and lymphatic filariasis rely on a bacterial endosymbiont, Wolbachia , which is a validated therapeutic target. Here, Clare et al. perform a high-throughput screen of 1.3 million compounds and identify 5 chemotypes with faster kill rates than existing anti- Wolbachia drugs.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 119/118 / 14/1 / 14/34 / 14/56 / 14/63 / 49/22 / 49/47 / 49/98 / 631/154/1435/2163 / 631/154/309/630 / 692/699/255/1715 / 692/700/565/1436/2774 / Aedes / Animals / Anthelmintic agents / Antibiotics / Antiparasitic agents / Cell Line / Consortia / Drug delivery systems / Drug development / Drug Discovery / Fecundity / Filariasis / Filaricides - analysis / High-throughput screening / High-Throughput Screening Assays / Humanities and Social Sciences / Informatics / multidisciplinary / Nematodes / Onchocerciasis / Organic chemistry / Science / Science (multidisciplinary) / Screening / Therapeutic applications / Tropical diseases / Vector-borne diseases / Wolbachia