Mammalian deubiquitinating enzyme inhibitors display

Simwela, N., Hughes, K. R., Rennie, M. T., Barrett, M. P. and Waters, A. P. (2021) Mammalian deubiquitinating enzyme inhibitors display. ACS Infectious Diseases, 7(2), pp. 333-346. (doi: 10.1021/acsinfecdis.0c00580) (PMID:33400499)

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Abstract

The ubiquitin proteasome system (UPS) is an emerging drug target in malaria due to its essential role in the parasite's life cycle stages as well its contribution to resistance to artemisinins. Polymorphisms in the gene of are primary markers of artemisinin resistance and among other things are phenotypically characterized by an overactive UPS. Inhibitors targeting the proteasome, critical components of the UPS, display activity in malaria parasites and synergize artemisinin action. Here we report the activity of small molecule inhibitors targeting mammalian deubiquitinating enzymes, DUBs (upstream UPS components), in malaria parasites. We show that generic DUB inhibitors can block intraerythrocytic development of malaria parasites and possess antiparasitic activity and can be used in combination with additive to synergistic effect. We also show that inhibition of these upstream components of the UPS can potentiate the activity of artemisinin as well as to the extent that artemisinin resistance can be overcome. Combinations of DUB inhibitors anticipated to target different DUB activities and downstream 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 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.

Item Type:Articles
Keywords:Artemisinin, malaria, potentiation, resistance, synergy, ubiquitin proteasome system.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Simwela, Nelson and Rennie, Mr Michael and Hughes, Dr Katie and Waters, Professor Andy and Barrett, Professor Michael
Authors: Simwela, N., Hughes, K. R., Rennie, M. T., Barrett, M. P., and Waters, A. P.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:ACS Infectious Diseases
Publisher:American Chemical Society
ISSN:2373-8227
ISSN (Online):2373-8227
Published Online:05 January 2021

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
143385Conditional translational repression: a core regulatory mechanism of gene expression during development of the malaria parasite.Andrew WatersWellcome Trust (WELLCOTR)083811/Z/07/ZIII - Parasitology
172459Gene expression in Plasmodium parasites: the molecular mechanics of gametocytogenesis (and variant transcription of genes)Andrew WatersWellcome Trust (WELLCOTR)107046/Z/15/ZIII - Parasitology
170547The Wellcome Centre for Molecular Parasitology ( Core Support )Andrew WatersWellcome Trust (WELLCOTR)104111/Z/14/ZRIII - Parasitology