A potent and selective reaction hijacking inhibitor of Plasmodium falciparum tyrosine tRNA synthetase exhibits single dose oral efficacy in vivo

SC Xie; CW Tai; CJ Morton; L Ma; SC Huang; S Wittlin; Y Du; Y Hu; C Dogovski; M Salimimarand; R Griffin; D England; ED la Cruz; I Deni; T Yeo; AY Burkhard; J Striepen; KA Schindler; B Crespo; FJ Gamo; Y Khandokar; CA Hutton; T Rabie; LM Birkholtz; MT Famodimu; MJ Delves; J Bolsher; KMJ Koolen; RV der Laak; ACC Aguiar; DB Pereira; RVC Guido; DJ Creek; DA Fidock; LR Dick; SL Brand; AE Gould; S Langston; MDW Griffin; L Tilley

Journal article

A potent and selective reaction hijacking inhibitor of Plasmodium falciparum tyrosine tRNA synthetase exhibits single dose oral efficacy in vivo

SC Xie, CW Tai, CJ Morton, L Ma, SC Huang, S Wittlin, Y Du, Y Hu, C Dogovski, M Salimimarand, R Griffin, D England, ED la Cruz, I Deni, T Yeo, AY Burkhard, J Striepen, KA Schindler, B Crespo, FJ Gamo Show all

Plos Pathogens | PUBLIC LIBRARY SCIENCE | Published : 2024

DOI: 10.1371/journal.ppat.1012429

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Abstract

The Plasmodium falciparum cytoplasmic tyrosine tRNA synthetase (PfTyrRS) is an attractive drug target that is susceptible to reaction-hijacking by AMP-mimicking nucleoside sulfamates. We previously identified an exemplar pyrazolopyrimidine ribose sulfamate, ML901, as a potent reaction hijacking inhibitor of PfTyrRS. Here we examined the stage specificity of action of ML901, showing very good activity against the schizont stage, but lower trophozoite stage activity. We explored a series of ML901 analogues and identified ML471, which exhibits improved potency against trophozoites and enhanced selectivity against a human cell line. Additionally, it has no inhibitory activity against human ubiqu..

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University of Melbourne Researchers

Stanley Xie Author

Craig Morton Author

Craig Hutton Author

Michael Griffin Author

Grants

Awarded by South African Medical Research Council

Funding Acknowledgements

Funding was provided by the Global Health Innovative Technology Fund, Japan (H2019- 104 to LT, LRD, SL, AEG), the Australian National Health and Medical Research Council (APP2022075 to LT), the Australian Research Council (DE230101173 to SCX), the Medicines for Malaria Venture (RD-19-001 to LMB; RD-08-0015 to DAF; RD-21-1003 to MJD), the Foundation for Research Support of the State of Sao Paulo (FAPESP; 2019/19708-0 and 2013/07600-3 to RVCG and ACCA), the South African Medical Research Council and the Department of Science and Innovation South African Research Chairs Initiative Grant managed by the National Research Foundation (UID 84627 to LMB), a Medical Research Council Career Development Award (MR/V010034/1 to MJD), and Millennium Pharmaceuticals, a wholly owned subsidiary of Takeda Pharmaceuticals Company Limited (LRD, SL, AEG). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.