Antimalarial proteasome inhibitor reveals collateral sensitivity from intersubunit interactions and fitness cost of resistance

Kirkman, Laura A.; Wen-hu, Zhan; Visone, Joseph E; Dziedziech, Alexis; Singh, Pradeep K.; Fan, Hao; Tong, Xinran; Bruzual, Igor; Hara, Ryujiro; Kawasaki, Masanori; Imaeda, Toshihiro; Okamoto, Rei; Sato, Kenjiro; Michino, Mayako; Álvaro, Elena Fernández; Guiang, Liselle F.; Sanz, Laura M.; Mota, Daniel J.; Govindasamy, Kavitha; Wang, Rong; Yan, Ling; Tumwebaze, Patrick K; Sukenick, George; Shi, Lei; Vendôme, Jérémie; Bhanot, Purnima; Rosenthal, Philip J.; Aso, Kazuyoshi; Foley, Michael A.; Cooper, Roland A.; Kafsack, Björn F.C.; Doggett, J. Stone; Nathan, Carl; Lin, Gang

doi:10.1073/pnas.1806109115

Cited by 82 publications

(131 citation statements)

References 42 publications

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“…This has indeed been recently illustrated where combined inhibition of the parasite β2 and β5 subunits of the parasites UPS has been shown to strongly synergize DHA activity. 51 In conclusion, our work confirms DUBs as potential druggable candidates in malaria parasites. Drug discovery programs take a long time, with for example a minimum of five years required to take a lead compound to a clinical candidate in malaria.…”

Section: Discussionsupporting

confidence: 73%

Mammalian deubiquitinating enzyme inhibitors displayin vitroandin vivoactivity against malaria parasites and potentiate artemisinin action

Simwela

Hughes

Rennie

et al. 2020

Preprint

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Current malaria control efforts rely significantly on artemisinin combinational therapies which have played massive roles in alleviating the global burden of the disease. Emergence of resistance to artemisinins is therefore, not just alarming but requires immediate intervention points such as development of new antimalarial drugs or improvement of the current drugs through adjuvant or combination therapies. Artemisinin resistance is primarily conferred by Kelch13 propeller mutations which are phenotypically characterised by generalised growth quiescence, altered haemoglobin trafficking and downstream enhanced activity of the parasite stress pathways through the ubiquitin proteasome system (UPS). Previous work on artemisinin resistance selection in a rodent model of malaria, which we and others have recently validated using reverse genetics, has also shown that mutations in deubiquitinating enzymes, DUBs (upstream UPS component) modulates susceptibility of malaria parasites to both artemisinin and chloroquine. The UPS or upstream protein trafficking pathways have, therefore, been proposed to be not just potential drug targets, but also possible intervention points to overcome artemisinin resistance. Here we report the activity of small molecule inhibitors targeting mammalian DUBs in malaria parasites. We show that generic DUB inhibitors can block intraerythrocytic development of malaria parasites in vitro and possess antiparasitic activity in vivo and can be used in combination with additive effect. We also show that inhibition of these upstream components of the UPS can potentiate the activity of artemisinin in vitro as well as in vivo to the extent that ART resistance can be overcome. Combinations of DUB inhibitors anticipated to target different DUB activities and downstream 20s proteasome inhibitors are even more effective at improving the potency of artemisinins than either inhibitors alone providing proof that targeting multiple UPS activities simultaneously could be an attractive approach to overcoming artemisinin resistance. These data further validate the parasite UPS as a target to both enhance artemisinin action and potentially overcome resistance. Lastly, we confirm that DUB inhibitors can be developed into in vivo antimalarial drugs with promise for activity against all of human malaria and could thus further exploit their current pursuit as anticancer agents in rapid drug repurposing programs.

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Section: Discussionsupporting

confidence: 73%

Mammalian deubiquitinating enzyme inhibitors displayin vitroandin vivoactivity against malaria parasites and potentiate artemisinin action

Simwela

Hughes

Rennie

et al. 2020

Preprint

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“…If so, this suggests treatment possibilities, as bacterial persister cells can be targeted by also inhibiting the integrated stress response (Cohen et al, 2013). Indeed, inhibiting the parasite proteasome can synergize with DHA and overcome ART resistance (Dogovski et al, 2015;Kirkman et al, 2018;Stokes et al, 2019). Inhibiting other stress response systems, such as protein-folding chaperones, should also be tested as potential combination therapies.…”

Section: Art-the Core Component Of Current First-line Antimalarial Comentioning

confidence: 99%

Elucidating Mechanisms of Drug-Resistant Plasmodium falciparum

Ross

Fidock

2019

Cell Host & Microbe

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Intensified treatment and control efforts since the early 2000s have dramatically reduced the burden of Plasmodium falciparum malaria. However, drug resistance threatens to derail this progress. In this review, we present four antimalarial resistance case studies that differ in timeline, technical approaches, mechanisms of action, and categories of resistance: chloroquine, sulfadoxine-pyrimethamine, artemisinin, and piperaquine. Lessons learned from prior losses of treatment efficacy, drug combinations, and control strategies will help advance mechanistic research into how P. falciparum parasites acquire resistance to current first-line artemisinin-based combination therapies. Understanding resistance in the clinic and laboratory is essential to prolong the effectiveness of current antimalarial drugs and to optimize the pipeline of future medicines.

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“…A recent report examined noncovalent asparagine ethylenediamine (AsnEDA) inhibitors and revealed good cellular selectivity, but this class of inhibitors is not stable in vivo (half-life of ∼30 min) and thus is not active (when used alone) in a mouse model of malaria. 11 If a potent, specific, and “drug-like” proteasome inhibitor could be identified, it would be a promising antimalarial compound in its own right and would be particularly effective in combination with artemisinins.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2018

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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 inhibitor features that enable retention of potent activity against the bortezomib-resistant line. Substrate profiling reveals P. falciparum 20S proteasome active site preferences that will inform attempts to design more selective inhibitors. This work provides a starting point for the identification of antimalarial drug leads that selectively target the P. falciparum proteasome.

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Antimalarial proteasome inhibitor reveals collateral sensitivity from intersubunit interactions and fitness cost of resistance

Cited by 82 publications

References 42 publications

Mammalian deubiquitinating enzyme inhibitors displayin vitroandin vivoactivity against malaria parasites and potentiate artemisinin action

Mammalian deubiquitinating enzyme inhibitors displayin vitroandin vivoactivity against malaria parasites and potentiate artemisinin action

Elucidating Mechanisms of Drug-Resistant Plasmodium falciparum

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

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