Inhibitors of ubiquitin E3 ligase as potential new antimalarial drug leads

Abstract Background Protein ubiquitylation is an important post-translational regulation, which has been shown to be necessary for life cycle progression and survival of Plasmodium falciparum. Ubiquitin is a highly conserved 76 amino acid polypeptide, which attaches covalently to target proteins thr...

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Main Authors:	Jagrati Jain, Surendra K. Jain, Larry A. Walker, Babu L. Tekwani
Format:	Article
Language:	English
Published:	BioMed Central 2017-06-01
Series:	BMC Pharmacology and Toxicology
Subjects:	Malaria Plasmodium falciparum Ubiquitine Proteasome Ubiquitine E3 ligase Antimalarial
Online Access:	http://link.springer.com/article/10.1186/s40360-017-0147-4

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spelling	doaj-art-e4c009e3971a4a668685a4aeaa4606742018-08-16T01:20:44ZengBioMed CentralBMC Pharmacology and Toxicology2050-65112017-06-0118111010.1186/s40360-017-0147-4Inhibitors of ubiquitin E3 ligase as potential new antimalarial drug leadsJagrati Jain0Surendra K. Jain1Larry A. Walker2Babu L. Tekwani3National Center for Natural Products Research, Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of MississippiNational Center for Natural Products Research, Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of MississippiNational Center for Natural Products Research, Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of MississippiNational Center for Natural Products Research, Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of MississippiAbstract Background Protein ubiquitylation is an important post-translational regulation, which has been shown to be necessary for life cycle progression and survival of Plasmodium falciparum. Ubiquitin is a highly conserved 76 amino acid polypeptide, which attaches covalently to target proteins through combined action of three classes of enzymes namely, the ubiquitin-activating enzyme (E1), ubiquitin-conjugating enzyme (E2) and ubiquitin-protein ligase (E3). Ubiquitin E1 and E2 are highly conserved within eukaryotes. However, the P. falciparum E3 ligase is substantially variable and divergent compared to the homologs from other eukaryotes, which make the E3 ligase a parasite-specific target. Methods A set of selected E3 ubiquitin ligase inhibitors was tested in vitro against a chloroquine-sensitive P. falciparum D6 strain (PfD6) and a chloroquine-resistant P. falciparum W2 strain (PfW2). The inhibitors were also tested against Vero and transformed THP1 cells for cytotoxicity. The lead antimalarial E3 ubiquitin ligase inhibitors were further evaluated for the stage-specific antimalarial action and effects on cellular development of P. falciparum in vitro. Statistics analysis was done by two-way ANOVA followed by Tukey and Sidak multiple comparison test using GraphPad Prism 6. Results E3 ligase inhibitors namely, JNJ 26854165, HLI 373 and Nutlin 3 showed prominent antimalarial activity against PfD6 and PfW2. These inhibitors were considerably less cytotoxic to mammalian Vero cells. JNJ 26854165, HLI 373 and Nutlin 3 blocked the development of P. falciparum parasite at the trophozoite and schizont stages, resulting in accumulation of distorted trophozoites and immature schizonts. Conclusions Interruption of trophozoites and schizont maturation by the antimalarial E3 ligase inhibitors suggest the role of ubiquitin/proteasome functions in the intraerythrocytic development of malaria parasite. The ubiquitin/proteasome functions may be critical for schizont maturation. Further investigations on the lead E3 ligase inhibitors shall provide better understanding regarding the importance of E3 ligase functions in the malaria parasite as a potential new antimalarial drug target and a new class of antimalarial drug leads.http://link.springer.com/article/10.1186/s40360-017-0147-4MalariaPlasmodium falciparumUbiquitineProteasomeUbiquitine E3 ligaseAntimalarial
institution	Open Data Bank
collection	Open Access Journals
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language	English
format	Article
author	Jagrati Jain Surendra K. Jain Larry A. Walker Babu L. Tekwani
spellingShingle	Jagrati Jain Surendra K. Jain Larry A. Walker Babu L. Tekwani Inhibitors of ubiquitin E3 ligase as potential new antimalarial drug leads BMC Pharmacology and Toxicology Malaria Plasmodium falciparum Ubiquitine Proteasome Ubiquitine E3 ligase Antimalarial
author_facet	Jagrati Jain Surendra K. Jain Larry A. Walker Babu L. Tekwani
author_sort	Jagrati Jain
title	Inhibitors of ubiquitin E3 ligase as potential new antimalarial drug leads
title_short	Inhibitors of ubiquitin E3 ligase as potential new antimalarial drug leads
title_full	Inhibitors of ubiquitin E3 ligase as potential new antimalarial drug leads
title_fullStr	Inhibitors of ubiquitin E3 ligase as potential new antimalarial drug leads
title_full_unstemmed	Inhibitors of ubiquitin E3 ligase as potential new antimalarial drug leads
title_sort	inhibitors of ubiquitin e3 ligase as potential new antimalarial drug leads
publisher	BioMed Central
series	BMC Pharmacology and Toxicology
issn	2050-6511
publishDate	2017-06-01
description	Abstract Background Protein ubiquitylation is an important post-translational regulation, which has been shown to be necessary for life cycle progression and survival of Plasmodium falciparum. Ubiquitin is a highly conserved 76 amino acid polypeptide, which attaches covalently to target proteins through combined action of three classes of enzymes namely, the ubiquitin-activating enzyme (E1), ubiquitin-conjugating enzyme (E2) and ubiquitin-protein ligase (E3). Ubiquitin E1 and E2 are highly conserved within eukaryotes. However, the P. falciparum E3 ligase is substantially variable and divergent compared to the homologs from other eukaryotes, which make the E3 ligase a parasite-specific target. Methods A set of selected E3 ubiquitin ligase inhibitors was tested in vitro against a chloroquine-sensitive P. falciparum D6 strain (PfD6) and a chloroquine-resistant P. falciparum W2 strain (PfW2). The inhibitors were also tested against Vero and transformed THP1 cells for cytotoxicity. The lead antimalarial E3 ubiquitin ligase inhibitors were further evaluated for the stage-specific antimalarial action and effects on cellular development of P. falciparum in vitro. Statistics analysis was done by two-way ANOVA followed by Tukey and Sidak multiple comparison test using GraphPad Prism 6. Results E3 ligase inhibitors namely, JNJ 26854165, HLI 373 and Nutlin 3 showed prominent antimalarial activity against PfD6 and PfW2. These inhibitors were considerably less cytotoxic to mammalian Vero cells. JNJ 26854165, HLI 373 and Nutlin 3 blocked the development of P. falciparum parasite at the trophozoite and schizont stages, resulting in accumulation of distorted trophozoites and immature schizonts. Conclusions Interruption of trophozoites and schizont maturation by the antimalarial E3 ligase inhibitors suggest the role of ubiquitin/proteasome functions in the intraerythrocytic development of malaria parasite. The ubiquitin/proteasome functions may be critical for schizont maturation. Further investigations on the lead E3 ligase inhibitors shall provide better understanding regarding the importance of E3 ligase functions in the malaria parasite as a potential new antimalarial drug target and a new class of antimalarial drug leads.
topic	Malaria Plasmodium falciparum Ubiquitine Proteasome Ubiquitine E3 ligase Antimalarial
url	http://link.springer.com/article/10.1186/s40360-017-0147-4
_version_	1612695039283036160

Inhibitors of ubiquitin E3 ligase as potential new antimalarial drug leads

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