Journal article
Aryl amino acetamides prevent Plasmodium falciparum ring development via targeting the lipid-transfer protein PfSTART1
MG Dans, C Boulet, GM Watson, W Nguyen, JM Dziekan, C Evelyn, K Reaksudsan, S Mehra, Z Razook, ND Geoghegan, MJ Mlodzianoski, CD Goodman, DB Ling, TK Jonsdottir, J Tong, MT Famodimu, M Kristan, H Pollard, LB Stewart, L Brandner-Garrod Show all
Nature Communications | NATURE PORTFOLIO | Published : 2024
Open access
Abstract
With resistance to most antimalarials increasing, it is imperative that new drugs are developed. We previously identified an aryl acetamide compound, MMV006833 (M-833), that inhibited the ring-stage development of newly invaded merozoites. Here, we select parasites resistant to M-833 and identify mutations in the START lipid transfer protein (PF3D7_0104200, PfSTART1). Introducing PfSTART1 mutations into wildtype parasites reproduces resistance to M-833 as well as to more potent analogues. PfSTART1 binding to the analogues is validated using organic solvent-based Proteome Integral Solubility Alteration (Solvent PISA) assays. Imaging of invading merozoites shows the inhibitors prevent the deve..
View full abstractGrants
Awarded by Medical Research Council
Funding Acknowledgements
We acknowledge the traditional custodians of the lands on which this project was conducted: the Wurundjeri and the Boon Wurrung people of the Kulin nation. We thank Lifeblood Biological Resources Australia for providing the human red blood cells and LifeArc for supplying ML10. We thank Danu Marapana for kindly sharing p1.2 CRISPR plasmid. We thank the WEHI screening facility for conducting parasite growth assays with newly synthesised compounds. This work was supported by the Victorian Operational Infrastructure Support Program received by the Walter and Eliza Hall and Burnet Institutes. This work was funded by the National Health and Medical Research Council of Australia (Ideas Grant to W.N. and P.G. 2001073; Development Grant 1135421 to B.E.S. and A.F.C.; Ideas Grant to K.L.R and N.D.G 2012271). A.F.C. is a Howard Hughes International Scholar and an Australia Fellow of the NHMRC. B.E.S. is a Corin Centenary Fellow. J.M.D. is a Human Frontier Science Program Fellow. MTF is supported by a grant from the Medicines for Malaria Venture (RD-21-2003) awarded to MJD. MJD is supported by a UKRI Medical Research Council Career Development Award (MR/V010034/1). Mass Spectrometry sample analysis was supported by WEHI Proteomics Facility. We thank Kirsty McCann for lending expertise on bioinformatic analyses of the resistant lines.