Journal article

Target Validation and Identification of Novel Boronate Inhibitors of the Plasmodium falciparum Proteasome

Stanley C Xie, David L Gillett, Natalie J Spillman, Christopher Tsu, Madeline R Luth, Sabine Ottilie, Sandra Duffy, Alexandra E Gould, Paul Hales, Benjamin A Seager, Carlie L Charron, Frank Bruzzese, Xiaofeng Yang, Xiansi Zhao, Shih-Chung Huang, Craig A Hutton, Jeremy N Burrows, Elizabeth A Winzeler, Vicky M Avery, Lawrence R Dick Show all

JOURNAL OF MEDICINAL CHEMISTRY | AMER CHEMICAL SOC | Published : 2018

Abstract

The Plasmodium proteasome represents a potential antimalarial drug target for compounds with activity against multiple life cycle stages. We screened a library of human proteasome inhibitors (peptidyl boronic acids) and compared activities against purified P. falciparum and human 20S proteasomes. We chose four hits that potently inhibit parasite growth and show a range of selectivities for inhibition of the growth of P. falciparum compared with human cell lines. P. falciparum was selected for resistance in vitro to the clinically used proteasome inhibitor, bortezomib, and whole genome sequencing was applied to identify mutations in the proteasome β5 subunit. Active site profiling revealed in..

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Grants

Awarded by National Health & Medical Research Council of Australia


Awarded by Global Health Innovation Technology Fund (GHIT)


Awarded by NIH


Awarded by Bill and Melinda Gates Foundations


Awarded by NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES


Funding Acknowledgements

We thank Dr. Paul Gilson, Prof. Brendan Crabb, and Dr. Mauro F. Azevedo, Burnet Institute, for the DD-GFP parasite line, Dr. Snigdha Tiash, Dr. Mike Griffin, and Riley Metcalfe, University of Melbourne, and Dr. Hua Liao, Dr. Hirotake Mizutani, Takeda Pharmaceuticals, and Dr. Stephen Brand, Medicines for Malaria Venture, for advice and technical support. We thank Dr. Greg Blatch and Eva-Rachele Pesce, Victoria University, for providing recombinant PfBiP. This work was supported by the National Health & Medical Research Council of Australia (Grants APP1092808, APP1072217) and the Global Health Innovation Technology Fund (GHIT Grant T2015-134). E.A.W. is supported by grants from the NIH (Grants 5R01A1090141 and R01AI103058) and by grants from the Bill and Melinda Gates Foundations (Grants OPP1086217, OPP1141300). We thank Medicines for Malaria Venture for ongoing support. We thank the Australian Red Cross Blood Bank for the provision of human red blood cells and serum.