A novel class of sulphonamides potently block malaria transmission by targeting a Plasmodium vacuole membrane protein
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
Phenotypic cell-based screens are critical tools for discovering candidate drugs for development, yet identification of the cellular target and mode of action of a candidate drug is often lacking. Using an imaging-based screen, we recently discovered an N-[(4-hydroxychroman-4-yl)methyl]-sulphonamide (N-4HCS) compound, DDD01035881, that blocks male gamete formation in the malaria parasite life cycle and subsequent transmission of the parasite to the mosquito with nanomolar activity. To identify the target(s) of DDD01035881, and of the N-4HCS class of compounds more broadly, we synthesised a photoactivatable derivative, probe 2. Photoaffinity labelling of probe 2 coupled with mass spectrometry identified the 16 kDa Plasmodium falciparum parasitophorous vacuole membrane protein Pfs16 as a potential parasite target. Complementary methods including cellular thermal shift assays confirmed that the parent molecule DDD01035881 stabilised Pfs16 in lysates from activated mature gametocytes. Combined with high-resolution, fluorescence and electron microscopy data, which demonstrated that parasites inhibited with N-4HCS compounds phenocopy the targeted deletion of Pfs16 in gametocytes, these data implicate Pfs16 as a likely target of DDD01035881. This finding establishes N-4HCS compounds as being flexible and effective starting candidates from which transmission-blocking antimalarials can be developed in the future.
Date Issued
2023-02-01
Date Acceptance
2022-12-13
Citation
Disease Models & Mechanisms, 2023, 16 (2), pp.1-20
ISSN
1754-8403
Publisher
The Company of Biologists
Start Page
1
End Page
20
Journal / Book Title
Disease Models & Mechanisms
Volume
16
Issue
2
Copyright Statement
© 2023. Published by The Company of Biologists Ltd
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
License URL
Identifier
https://journals.biologists.com/dmm/article/16/2/dmm049950/286739/A-novel-class-of-sulphonamides-potently-block
Publication Status
Published online
Date Publish Online
2023-01-30