Road Towards Development of New Antimalarial: Organelle Associated Metabolic Pathways in Plasmodium as Drug Targets and Discovery of Lead Drug Candidates

Asad, Mohd; Muneer, Azhar; Kumar, Pradeep; Thakur, Vandana; Rathore, Sumit; Malhotra, Pawan; Mohmmed, Asif

doi:10.1007/978-981-32-9449-3_10

Cited by 2 publications

(2 citation statements)

References 193 publications

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“…We have earlier shown that the P. falciparum ClpQ, Pf ClpQ, harbours threonine protease activity; further the Pf ClpQ protease is localized in the parasite mitochondria (9, 10). Indeed, parasite proteases, especially organelle protease, are considered as important drug targets (16–21). Detailed studies by our group including a trans-dominant negative approach clearly showed that Pf ClpQ is essential for the parasite survival (9, 11); further these studies showed that the Pf ClpQ plays a key role in development of functional mitochondria and its segregation.…”

Section: Discussionmentioning

confidence: 99%

Small-molecule inhibitors targeting prokaryotic ClpQ protease in Plasmodium display anti-malarial efficacies against blood and liver stages

Jain

Asad

Caldelari

et al. 2022

Preprint

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The ATP-dependent ClpQY system is a prokaryotic proteasome-like machinery in the mitochondrion of malaria parasite, Plasmodium. This protease system is identified as a validated target for malaria intervention. Here we have identified drug-like small chemical compounds, pyrimidotriazine derivatives, as specific inhibitors of P. falciparum ClpQ (PfClpQ) having effective parasiticidal efficacies on asexual and liver stages. Screening of the ‘Malaria Box’ compound library, using a robust in vitro activity assay, identified a hit compound targeting the PfClpQ protease with IC50 at ~750nM. Further, Structure-Activity Relationship (SAR) analysis, using a small library of derivatives of the hit compound, identified three potential lead compounds, ICGEB-L1, ICGEB-L2 and ICGEB-L3, which inhibited enzyme activity with IC50 in 100-200nM ranges. The three lead compounds effectively inhibited in vitro asexual stage parasite growth in similar concentration ranges with ~100-fold selectivity over mammalian cell line; in addition, these compounds effectively inhibited in vitro growth and maturation of hepatocytic stage parasites with EC50 in low nano-molar ranges. These compounds were found to effectively block the development of trophozoite stages to schizont stage, concurrently arresting development and segregation of parasite mitochondria, in asexual as well as hepatocytic stages of the parasite. These morphological and developmental effects of the drugs on parasites mimic the data from genetic ablation of PfClpQ. Importantly, all three compounds showed significant in vivo anti-parasitic efficacies on blood stages of P. berghei mouse malaria model. Overall these results suggest that these PfClpQ targeting compounds are promising candidates to develop new anti-malarials.

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Section: Discussionmentioning

confidence: 99%

Small-molecule inhibitors targeting prokaryotic ClpQ protease in Plasmodium display anti-malarial efficacies against blood and liver stages

Jain

Asad

Caldelari

et al. 2022

Preprint

Self Cite

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“…Te SUF pathway is important to the malaria parasite as it provides the Fe-S cluster necessary for the activity of several proteins, including dihydrolipoyl dehydrogenase, glyoxalase I-like protein, ferredoxin, antioxidant protein, glutathione reductase, lipoic acid synthase (LipA), (dimethylallyl)adenosine tRNA methylthiotransferase, and also the methylerythritol phosphate (MEP) pathway enzymes ((E)-4-hydroxy-3-methylbut-2-en-1-yl diphosphate synthase (IspG) and (E)-4-hydroxy-3-methylbut-2-en-1-yl diphosphate reductase (IspH)) [35,55]. Te Fe-S synthetic pathway is important during the sexual stage of the parasite's development; hence, discovering new and potent inhibitors against this stage is important to arrest the parasite's lifecycle and reduce malaria transmission [56].…”

Section: Suf Pathwaymentioning

confidence: 99%

Apicoplast-Resident Processes: Exploiting the Chink in the Armour of Plasmodium falciparum Parasites

Mamudu,

Tebamifor,

Sule

et al. 2024

Advances in Pharmacological and Pharmaceutical Sciences

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The discovery of a relict plastid, also known as an apicoplast (apicomplexan plastid), that houses housekeeping processes and metabolic pathways critical to Plasmodium parasites’ survival has prompted increased research on identifying potent inhibitors that can impinge on apicoplast-localised processes. The apicoplast is absent in humans, yet it is proposed to originate from the eukaryote’s secondary endosymbiosis of a primary symbiont. This symbiotic relationship provides a favourable microenvironment for metabolic processes such as haem biosynthesis, Fe-S cluster synthesis, isoprenoid biosynthesis, fatty acid synthesis, and housekeeping processes such as DNA replication, transcription, and translation, distinct from analogous mammalian processes. Recent advancements in comprehending the biology of the apicoplast reveal it as a vulnerable organelle for malaria parasites, offering numerous potential targets for effective antimalarial therapies. We provide an overview of the metabolic processes occurring in the apicoplast and discuss the organelle as a viable antimalarial target in light of current advances in drug discovery. We further highlighted the relevance of these metabolic processes to Plasmodium falciparum during the different stages of the lifecycle.

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Road Towards Development of New Antimalarial: Organelle Associated Metabolic Pathways in Plasmodium as Drug Targets and Discovery of Lead Drug Candidates

Cited by 2 publications

References 193 publications

Small-molecule inhibitors targeting prokaryotic ClpQ protease in Plasmodium display anti-malarial efficacies against blood and liver stages

Small-molecule inhibitors targeting prokaryotic ClpQ protease in Plasmodium display anti-malarial efficacies against blood and liver stages

Apicoplast-Resident Processes: Exploiting the Chink in the Armour of Plasmodium falciparum Parasites

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