BibTex format
@article{Yahiya:2023:10.1242/dmm.049950,
author = {Yahiya, S and Saunders, CN and Hassan, S and Straschil, U and Fischer, OJ and Rueda-Zubiaurre, A and Haase, S and Vizcay-Barrena, G and Famodimu, MT and Jordan, S and Delves, MJ and Tate, EW and Barnard, A and Fuchter, MJ and Baum, J},
doi = {10.1242/dmm.049950},
journal = {Disease Models & Mechanisms},
pages = {1--20},
title = {A novel class of sulphonamides potently block malaria transmission by targeting a Plasmodium vacuole membrane protein},
url = {http://dx.doi.org/10.1242/dmm.049950},
volume = {16},
year = {2023}
}
RIS format (EndNote, RefMan)
TY - JOUR
AB - 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 16kDa 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.
AU - Yahiya,S
AU - Saunders,CN
AU - Hassan,S
AU - Straschil,U
AU - Fischer,OJ
AU - Rueda-Zubiaurre,A
AU - Haase,S
AU - Vizcay-Barrena,G
AU - Famodimu,MT
AU - Jordan,S
AU - Delves,MJ
AU - Tate,EW
AU - Barnard,A
AU - Fuchter,MJ
AU - Baum,J
DO - 10.1242/dmm.049950
EP - 20
PY - 2023///
SN - 1754-8403
SP - 1
TI - A novel class of sulphonamides potently block malaria transmission by targeting a Plasmodium vacuole membrane protein
T2 - Disease Models & Mechanisms
UR - http://dx.doi.org/10.1242/dmm.049950
UR - https://journals.biologists.com/dmm/article/16/2/dmm049950/286739/A-novel-class-of-sulphonamides-potently-block
UR - http://hdl.handle.net/10044/1/101971
VL - 16
ER -