A Click Chemistry‐Based Proteomic Approach Reveals that 1,2,4‐Trioxolane and Artemisinin Antimalarials Share a Common Protein Alkylation Profile

Ismail, Hanafy M.; Barton, Victoria; Panchana, Matthew; Charoensutthivarakul, Sitthivut; Biagini, Giancarlo A.; Ward, Stephen A.; O’Neill, Paul M.

doi:10.1002/anie.201512062

Cited by 78 publications

(90 citation statements)

References 25 publications

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“…First, Plasmodium parasites require the proteasome to progress through their complex lifecycle and a number of different classes of inhibitors have been shown to block growth or kill parasite at all lifecycle stages including the transmissive gametocyte stages [9–18]. Second, proteins damaged by indiscriminate protein alkylation caused by the antimalarial action of endoperoxides such as ART and the newer synthetic ozonides (OZ277, OZ439) that mimic artemisinin action [22–24] must be degraded to maintain homeostasis. The proteasome carries the largest burden of protein degradation, and has been the best characterized of the various degradative systems in Plasmodium .…”

Section: Combating Drug-resistant Malaria: Upsetting the Proteostaticmentioning

confidence: 99%

“…ART and synthetic ozonides alkylate proteins that are involved in a wide variety of cellular processes, including hemoglobin degradation, antioxidant responses, and stress pathways [22–24]. Recent evidence suggests that ART-treated parasites accumulate ubiquitinated polypeptides [25], providing an increased load of proteins that require degradation.…”

Section: Combating Drug-resistant Malaria: Upsetting the Proteostaticmentioning

confidence: 99%

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Protein Degradation Systems as Antimalarial Therapeutic Targets

Fidock

Bogyo

2017

Trends in Parasitology

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Artemisinin (ART)-based combination therapies are the most efficacious treatment of non-complicated Plasmodium falciparum infection. Alarmingly, P. falciparum strains have acquired resistance to ART in Southeast Asia and Africa. ART creates widespread protein and lipid damage inside intra-erythrocytic parasites, necessitating macromolecule degradation. The proteasome is the main engine of Plasmodium protein degradation. Indeed, proteasome inhibition and ART synergized in ART-resistant parasites. Moreover, ubiquitin modification is associated with resistance to multiple antimalarials. Targeting the ubiquitin-proteasome system, therefore, is an attractive avenue to combat drug resistance. Here, we review recent advances leading to specific targeting of the Plasmodium proteasome. We also highlight the potential for targeting other non-proteasomal protein degradation systems as an additional strategy to disrupt protein homeostasis.

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Section: Combating Drug-resistant Malaria: Upsetting the Proteostaticmentioning

confidence: 99%

Section: Combating Drug-resistant Malaria: Upsetting the Proteostaticmentioning

confidence: 99%

Protein Degradation Systems as Antimalarial Therapeutic Targets

Fidock

Bogyo

2017

Trends in Parasitology

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“…Understanding the mechanism of action of both the artemisinins and the ozonides is an active area of research. Various biochemical and biomimetic approaches have been utilized to identify both the molecular targets of peroxide antimalarials and parasite biochemical pathways perturbed in response to drug treatment (29,(39)(40)(41)(42). Many of these in vitro techniques require the use of specific conditions such as high parasitemia (39,40,42,43) for optimal assay performance, and these conditions differ considerably from those used in typical in vitro drug activity measurements.…”

mentioning

confidence: 99%

Parasite-Mediated Degradation of Synthetic Ozonide Antimalarials Impacts In Vitro Antimalarial Activity

Giannangelo

Stingelin

Yang

et al. 2018

Antimicrob Agents Chemother

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The peroxide bond of the artemisinins inspired the development of a class of fully synthetic 1,2,4-trioxolane-based antimalarials, collectively known as the ozonides. Similar to the artemisinins, heme-mediated degradation of the ozonides generates highly reactive radical species that are thought to mediate parasite killing by damaging critical parasite biomolecules. We examined the relationship between parasite dependent degradation and antimalarial activity for two ozonides, OZ277 (arterolane) and OZ439 (artefenomel), using a combination of drug stability and pulsed-exposure activity assays. Our results showed that drug degradation is parasite stage dependent and positively correlates with parasite load. Increasing trophozoite-stage parasitemia leads to substantially higher rates of degradation for both OZ277 and OZ439, and this is associated with a reduction in antimalarial activity. Under conditions of very high parasitemia (∼90%), OZ277 and OZ439 were rapidly degraded and completely devoid of activity in trophozoite-stage parasite cultures exposed to a 3-h drug pulse. This study highlights the impact of increasing parasite load on ozonide stability and antimalarial activity and should be considered when investigating the antimalarial mode of action of the ozonide antimalarials under conditions of high parasitemia.

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“…[4][5][6] Recently,i tw as shown that artemisinins are ligands of the mammalian protein gephyrin [7] and that the mechanism of action of these molecules depends on the enhancement of GABA-A receptor signaling,which leads to the regeneration of pancreatic bcells from a-cells in aR OS-independent manner.T herefore, artemisinins may also find application in the treatment of diabetes mellitus.I na ddition, Lisewski et al [8] reported that the Plasmodium falciparum antigen EXP1, am embrane glutathione S-transferase,i sp otently inhibited by artesunate in acompetitive mode.Despite all this,the exact nature of the mechanism and the molecular target, as well as whether the action of artemisinins is stereospecific,remain elusive and are still under debate. [9,10] Herein, we show that the antimalarial activity of artemisinin is not stereospecific,and ageneral and straightforward approach to this natural endoperoxide is presented that enables the synthesis of artemisinin derivatives that are not accessible by applying current methods.S everal proteins have been reported to be the targets of this sesquiterpene lactone.R ecently,i dentification of ap lethora of artemisinin-binding proteins of Plasmodium falciparum was reported by Wang et al [11,12] Similar studies were also carried out by Ismail et al [13] Therefore,t he hypothesis that artemisinin interacts with as pecific protein of Plasmodium falciparum is questionable as described by Fügi et al [14] Furthermore,a ccording to investigations of ONeill et al, artemisinin activity against this parasite is not stereospecific. [15] To unequivocally answer this question, investigation of the biological activity of (À)-artemisinin (1;t he antipode of natural (+ +)-artemisinin) is absolutely necessary.…”

mentioning

confidence: 77%

Total Synthesis and Biological Investigation of (−)‐Artemisinin: The Antimalarial Activity of Artemisinin Is not Stereospecific

et al. 2018

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Here, we describe an efficient and diversity-oriented entry to both (-)-artemisinin (1) and its natural antipode (+)-artemisinin, starting from commercially and readily available S-(+)- and R-(-)-citronellene, respectively. Subsequently, we answered the still open question regarding the specificity of artemisinins action. By using a drug-sensitive Plasmodium falciparum NF54 strain, we showed that the antimalarial activity of artemisinin is not stereospecific. Our straightforward and biomimetic approach to this natural endoperoxide enables the synthesis of artemisinin derivatives that are not accessible through applying current methods and may help to address the problem of emerging resistance of Plasmodium falciparum towards artemisinin.

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A Click Chemistry‐Based Proteomic Approach Reveals that 1,2,4‐Trioxolane and Artemisinin Antimalarials Share a Common Protein Alkylation Profile

Cited by 78 publications

References 25 publications

Protein Degradation Systems as Antimalarial Therapeutic Targets

Protein Degradation Systems as Antimalarial Therapeutic Targets

Parasite-Mediated Degradation of Synthetic Ozonide Antimalarials Impacts In Vitro Antimalarial Activity

Total Synthesis and Biological Investigation of (−)‐Artemisinin: The Antimalarial Activity of Artemisinin Is not Stereospecific

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