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Identification and prioritization of novel anti-Wolbachia chemotypes from screening a 10,000-compound diversity library

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Johnston, Kelly, Cook, Darren, Berry, Neil, Hong, Weiqian David, Clare, Rachel ORCID: https://orcid.org/0000-0002-3945-0530, Goddard, Megan, Ford, Louise, Nixon, Gemma, O'Neill, Paul, Ward, Steve ORCID: https://orcid.org/0000-0003-2331-3192 and Taylor, Mark (2017) 'Identification and prioritization of novel anti-Wolbachia chemotypes from screening a 10,000-compound diversity library'. Science Advances, Vol 3, Issue 9, eaao1551.

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Abstract

Lymphatic filariasis and onchocerciasis are two important neglected tropical diseases (NTDs) that cause severe disability. Control efforts are hindered by the lack of a safe macrofilaricidal drug. Targeting the Wolbachia bacterial endosymbionts in these parasites with doxycycline leads to a macrofilaricidal outcome, but protracted treatment regimens and contraindications restrict its widespread implementation. The Anti-Wolbachia consortium aims to develop improved anti-Wolbachia drugs to overcome these barriers. We describe the first screening of a large, diverse compound library against Wolbachia. This whole-organism screen, streamlined to reduce bottlenecks, produced a hit rate of 0.5%. Chemoinformatic analysis of the top 50 hits led to the identification of six structurally diverse chemotypes, the disclosure of which could offer interesting avenues of investigation to other researchers active in this field. An example of hit-to-lead optimization is described to further demonstrate the potential of developing these high-quality hit series as safe, efficacious, and selective anti-Wolbachia macrofilaricides.

Item Type: Article
Subjects: QX Parasitology > Arthropods > QX 460 Arthropods
QX Parasitology > Insects. Other Parasites > QX 650 Insect vectors
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/10.1126/sciadv.aao1551
Depositing User: Stacy Murtagh
Date Deposited: 28 Sep 2017 15:55
Last Modified: 29 Sep 2017 09:18
URI: http://archive.lstmed.ac.uk/id/eprint/7644

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