Journal article
Design of proteasome inhibitors with oral efficacy in vivo against Plasmodium falciparum and selectivity over the human proteasome
SC Xie, RD Metcalfe, H Mizutani, T Puhalovich, E Hanssen, CJ Morton, Y Du, C Dogovski, SC Huang, J Ciavarri, P Hales, RJ Griffin, LH Cohen, BC Chuang, S Wittlin, I Deni, T Yeo, KE Ward, DC Barry, B Liu Show all
Proceedings of the National Academy of Sciences of the United States of America | Published : 2021
Abstract
The Plasmodium falciparum proteasome is a potential antimalarial drug target. We have identified a series of amino-amide boronates that are potent and specific inhibitors of the P. falciparum 20S proteasome (Pf20S) β5 active site and that exhibit fast-acting antimalarial activity. They selectively inhibit the growth of P. falciparum compared with a human cell line and exhibit high potency against field isolates of P. falciparum and Plasmodium vivax. They have a low propensity for development of resistance and possess liver stage and transmission-blocking activity. Exemplar compounds, MPI-5 and MPI-13, show potent activity against P. falciparum infections in a SCID mouse model with an oral do..
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Grants
Awarded by Takeda Pharmaceutical Company
Funding Acknowledgements
We thank the following colleagues: HepG2 toxicity assays: Lorna Campbell, Nicole Mutter, and Irene Hallyburton, University of Dundee; Anirban Koley, Pranab Dhar, and Partha Mukherjee, TCG Lifesciences;. Pf and P. vivax ex vivo patient isolate schizonts from the Brazilian Amazon: Dhelio B. Pereira and Carolina Bioni; liver-stage in vitro assays: Rianne van der Laak and Angelika Sturm, TropIQ Health Sciences; support with the SCID mouse and panel assays: Ursula Lehmann and Christian Scheurer, Swiss Tropical and Public Health Institute; support with the bioanalytical determination and PK evaluation in mouse blood samples: Anita Kress, Iris Barme, Mark Enzler, and Christoph Siethoff, Swiss BioQuant; assistance with whole-genome sequencing and analysis: Sachel Mok and AnneCatrin Uhlemann, Columbia University; cryo-EM data acquisition: Andrew Leis, University of Melbourne; and useful advice: Steven Langston and Yongbo Hu, Takeda Pharmaceuticals. The cryo-EM work was performed in the Bio21 Ian Holmes Imaging Centre. We thank the Global Health Innovative Technology Fund (H2019-101), the Australian National Health and Medical Research Council, MMV, and Millennium Pharmaceuticals, a wholly owned subsidiary of Takeda Pharmaceuticals Company Limited, for research support. J.B. is supported by an Investigator Award from Wellcome (100993/B/13/Z) and MMV RD-08-2800. M.W.P. is a National Health and Medical Research Council of Australia Research Fellow (APP1117183) and Investigator (APP1194263). L.T. is supported by an Australian Research Council Laureate Fellowship. Funding from the Victorian Government Operational Infrastructure Support Scheme to St Vincent's Institute is acknowledged. D.A.F. kindly acknowledges funding support from NIH (R33 AI127581). E.A.W. and S.O. are supported by MMV RD-12-0096. R.V.C.G. thanks the Sao Paulo Research Foundation (FAPESP), for funding the research (Centros de Pesquisa, Inovacao e Difusao [CEPID] grants 2013/07600-3 and 2020/12904-5). A.C.C.A. and R.V.C.G. are supported by MMV RD-16-1066. The Talos Artica electron microscope was purchased with the help of an Australian Research Council Linkage Infrastructure, Equipment and Facilities grant led by M.W.P.