Hundreds of dual-stage antimalarial molecules discovered by a functional gametocyte screen

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Title: Hundreds of dual-stage antimalarial molecules discovered by a functional gametocyte screen
Author(s): Miguel-Blanco, C
Molina, I
Bardera, AI
Diaz, B
De las Heras, L
Lozano, S
Gonzalez, C
Rodrigues, J
Delves, MJ
Ruecker, A
Colmenarejo, G
Viera, S
Martinez-Martinez, MS
Fernandez, E
Baum, J
Sinden, RE
Herreros, E
Item Type: Journal Article
Abstract: Plasmodium falciparum stage V gametocytes are responsible for parasite transmission, and drugs targeting this stage are needed to support malaria elimination. We here screen the Tres Cantos Antimalarial Set (TCAMS) using the previously developed P. falciparum female gametocyte activation assay (Pf FGAA), which assesses stage V female gametocyte viability and functionality using Pfs25 expression. We identify over 400 compounds with activities <2 μM, chemically classified into 57 clusters and 33 singletons. Up to 68% of the hits are chemotypes described for the first time as late-stage gametocyte-targeting molecules. In addition, the biological profile of 90 compounds representing the chemical diversity is assessed. We confirm in vitro transmission-blocking activity of four of the six selected molecules belonging to three distinct scaffold clusters. Overall, this TCAMS gametocyte screen provides 276 promising antimalarial molecules with dual asexual/sexual activity, representing starting points for target identification and candidate selection.
Publication Date: 17-May-2017
Date of Acceptance: 3-Mar-2017
URI: http://hdl.handle.net/10044/1/49100
DOI: https://dx.doi.org/10.1038/ncomms15160
ISSN: 2041-1723
Publisher: Nature Publishing Group
Journal / Book Title: Nature Communications
Volume: 8
Copyright Statement: © The Author(s) 2017. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
Sponsor/Funder: Bill & Melinda Gates Foundation
Bill & Melinda Gates Foundation
Medicines for Malaria Venture
Funder's Grant Number: OPP1043501
GAT.0888-11-06546-COL
MMV08/2800
Keywords: Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
PLASMODIUM-FALCIPARUM MALARIA
STARTING POINTS
TRANSMISSION
ASSAY
DRUGS
PRIMAQUINE
IDENTIFICATION
RESPONSES
PARASITES
IDENTIFY
Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
PLASMODIUM-FALCIPARUM MALARIA
STARTING POINTS
TRANSMISSION
ASSAY
DRUGS
PRIMAQUINE
IDENTIFICATION
RESPONSES
PARASITES
IDENTIFY
MD Multidisciplinary
Publication Status: Published
Article Number: ARTN 15160
Appears in Collections:Faculty of Natural Sciences



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