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



Johnston, Kelly L, Cook, Darren AN, Berry, Neil G ORCID: 0000-0003-1928-0738, Hong, W David, Clare, Rachel H, Goddard, Megan, Ford, Louise, Nixon, Gemma L, O'Neill, Paul M ORCID: 0000-0003-4338-0317, Ward, Stephen A
et al (show 1 more authors) (2017) Identification and prioritization of novel anti-Wolbachia chemotypes from screening a 10,000-compound diversity library. SCIENCE ADVANCES, 3 (09).

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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
Depositing User: Symplectic Admin
Date Deposited: 04 Oct 2017 10:35
Last Modified: 16 Apr 2021 11:23
DOI: 10.1126/sciadv.aao1551
Related URLs:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3009765