Industrial scale high-throughput screening delivers multiple fast acting macrofilaricides

Clare, Rachel ORCID: https://orcid.org/0000-0002-3945-0530, Bardelle, Catherine, Harper, Paul, Hong, Weiqian, Borjesson, Ulf, Johnston, Kelly, Collier, Matthew, Myhill, Laura, Cassidy, Andrew, Plant, Darren, Plant, Helen, Clark, Roger, Cook, Darren, Steven, Andrew, Archer, John, McGillan, Paul, Charoensutthivarakul, Sitthivut, Bibby, Jaclyn, Sharma, Raman, Nixon, Gemma, Slatko, Barton, Cantin, Lindsey, Wu, Bo, Turner, Joseph ORCID: https://orcid.org/0000-0002-2185-5476, Ford, Louise, Rich, Kirsty, Wigglesworth, Mark, Berry, Neil, O'Neill, Paul, Taylor, Mark ORCID: https://orcid.org/0000-0003-3396-9275 and Ward, Steve ORCID: https://orcid.org/0000-0003-2331-3192 (2019) 'Industrial scale high-throughput screening delivers multiple fast acting macrofilaricides'. Nature Communications, Vol 10, Issue 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
Subjects:	QV Pharmacology > Anti-Inflammatory Agents. Anti-Infective Agents. Antineoplastic Agents > QV 253 Anthelmintics WA Public Health > Preventive Medicine > WA 110 Prevention and control of communicable diseases. Transmission of infectious diseases WA Public Health > Preventive Medicine > WA 243 Diagnositic services WA Public Health > Health Administration and Organization > WA 540 National and state health administration WC Communicable Diseases > Tropical and Parasitic Diseases > WC 880 Filariasis and related conditions (General) WC Communicable Diseases > Tropical and Parasitic Diseases > WC 885 Onchocerciasis
Faculty: Department:	Biological Sciences > Department of Tropical Disease Biology
Digital Object Identifer (DOI):	https://doi.org/10.1038/s41467-018-07826-2
Depositing User:	Stacy Murtagh
Date Deposited:	04 Jan 2019 10:38
Last Modified:	16 Sep 2019 09:01
URI:	https://archive.lstmed.ac.uk/id/eprint/9926

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