Nature communications · 2019
Industrial scale high-throughput screening delivers multiple fast acting macrofilaricides.
Оценочное исследованиеСтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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Clare Rachel H, Bardelle Catherine, Harper Paul, Hong W David, Börjesson Ulf, Johnston Kelly L, Collier Matthew, Myhill Laura, Cassidy Andrew, Plant Darren, Plant Helen, Clark Roger, Cook Darren A N, 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, O'Neill Paul M, Taylor Mark J, Ward Stephen A
Аннотация
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.