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.
journal_name
Sci Advjournal_title
Science advancesauthors
Johnston KL,Cook DAN,Berry NG,David Hong W,Clare RH,Goddard M,Ford L,Nixon GL,O'Neill PM,Ward SA,Taylor MJdoi
10.1126/sciadv.aao1551subject
Has Abstractpub_date
2017-09-27 00:00:00pages
eaao1551issue
9issn
2375-2548pii
aao1551journal_volume
3pub_type
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