A high throughput screen for next-generation leads targeting malaria parasite transmission

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Title: A high throughput screen for next-generation leads targeting malaria parasite transmission
Authors: Delves, M
Miguel-Blanco, C
Matthews, H
Molina, I
Ruecker, A
Yahiya, S
Straschil, U
Abraham, M
Leon-Diaz, ML
Fischer, O
Zubiaurre, A
Brandt, J
Cortes, A
Barnard, A
Fuchter, M
Calderon, F
Winzeler, E
Sinden, R
Herreros, E
Gamo, FJ
Baum, J
Item Type: Journal Article
Abstract: Spread of parasite resistance to artemisinin threatens current frontline antimalarial therapies, highlighting the need for new drugs with alternative modes of action. Since only 0.2–1% of asexual parasites differentiate into sexual, transmission-competent forms, targeting this natural bottleneck provides a tangible route to interrupt disease transmission and mitigate resistance selection. Here we present a high-throughput screen of gametogenesis against a ~70,000 compound diversity library, identifying seventeen drug-like molecules that target transmission. Hit molecules possess varied activity profiles including male-specific, dual acting male–female and dual-asexual-sexual, with one promising N-((4-hydroxychroman-4-yl)methyl)-sulphonamide scaffold found to have sub-micromolar activity in vitro and in vivo efficacy. Development of leads with modes of action focussed on the sexual stages of malaria parasite development provide a previously unexplored base from which future therapeutics can be developed, capable of preventing parasite transmission through the population.
Issue Date: 18-Sep-2018
Date of Acceptance: 26-Jul-2018
URI: http://hdl.handle.net/10044/1/62850
DOI: https://dx.doi.org/10.1038/s41467-018-05777-2
ISSN: 2041-1723
Publisher: Nature Publishing Group
Journal / Book Title: Nature Communications
Volume: 9
Copyright Statement: © The Author(s) 2018. s This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/ licenses/by/4.0/
Sponsor/Funder: Bill & Melinda Gates Foundation
Wellcome Trust
Wellcome Trust
Engineering & Physical Science Research Council (EPSRC)
Funder's Grant Number: OPP1043501
100993/Z/13/Z
100993/Z/13/Z
EP/L014580/1
Keywords: MD Multidisciplinary
Publication Status: Published
Article Number: 3805
Appears in Collections:Chemistry
Faculty of Natural Sciences



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