PROTEASOME INHIBITORS AS REVERSERS OF RESISTANCE TO ARTEMISININ-BASED ANTIMALARIALS

Grant number: 1092808 | Funding period: 2015 - 2017

Completed

Abstract

Current antimalarial control is highly dependent on Artemisinin Combination Therapy (ACTs), which makes recent reports of decreased clinical efficacy of artemisinins extremely concerning. This project will develop proteasome inhibitors to synergise the activity of artemisinins - effectively reversing resistance. We will confirm that the selected compounds have good bioavailability, low cytotoxicity in human cell lines and efficacy in mouse models of malaria.

Related publications (4)

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The structure of the PA28-20S proteasome complex from Plasmodium falciparum and implications for proteostasis

Stanley C Xie, Riley D Metcalfe, Eric Hanssen, Tuo Yang, David L Gillett, Andrew P Leis, Craig J Morton, Michael J Kuiper, Michael W Parker, Natalie J Spillman, Wilson Wong, Christopher Tsu, Lawrence R Dick, Michael DW Griffin, Leann Tilley

2019-11-01

The activity of the proteasome 20S catalytic core is regulated by protein complexes that bind to one or both ends. The PA28 regula..

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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

2018-11-22

The Plasmodium proteasome represents a potential antimalarial drug target for compounds with activity against multiple life cycle ..

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Comparison of the Exposure Time Dependence of the Activities of Synthetic Ozonide Antimalarials and Dihydroartemisinin against K13 Wild-Type and Mutant Plasmodium falciparum Strains

Tuo Yang, Stanley C Xie, Pengxing Cao, Carlo Giannangelo, James McCaw, Darren J Creek, Susan A Charman, Nectarios Klonis, Leann Tilley

2016-08-01

Fully synthetic endoperoxide antimalarials, namely, OZ277 (RBx11160; also known as arterolane) and OZ439 (artefenomel), have been ..

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Haemoglobin degradation underpins the sensitivity of early ring stage Plasmodium falciparum to artemisinins

Stanley C Xie, Con Dogovski, Eric Hanssen, Francis Chiu, Tuo Yang, Maria P Crespo, Che Stafford, Steven Batinovic, Silvia Teguh, Susan Charman, Nectarios Klonis, Leann Tilley

2016-01-15

Current first-line artemisinin antimalarials are threatened by the emergence of resistant Plasmodium falciparum. Decreased sensiti..

University of Melbourne Researchers