Discovery of small molecule inhibitors of Plasmodium falciparum apicoplast DNA polymerase

Kaur, Supreet; Nieto, Nicholas; McDonald, Peter R.; Beck, Josh R.; Honzatko, Richard B.; Roy, Anuradha; Nelson, Scott W.

doi:10.1080/14756366.2022.2070909

Cited by 10 publications

(9 citation statements)

References 33 publications

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“…Therefore, although steady-state experiments remain an excellent starting point for the preliminary characterization of a DNA polymerase, the kinetic information derived from these assays typically do not represent the kinetics followed by this enzyme in vivo and frequently underestimate the effects of altered substrates on polymerase kinetics. 18 ■ CONCLUSIONS AND FUTURE DIRECTIONS Owing to apPol's putative function as the only apicoplast polymerase, inhibiting polymerase activity has been proposed to be a viable approach to treat malaria, 12,65,66 and the kinetic characterization presented here lays down the foundation for future structure−function correlation studies with this therapeutically relevant enzyme. Each reaction intermediate described in the catalytic cycle of apPol here represents a potential drug target.…”

Section: ■ Discussionmentioning

confidence: 90%

“…Owing to apPol’s putative function as the only apicoplast polymerase, inhibiting polymerase activity has been proposed to be a viable approach to treat malaria, ,, and the kinetic characterization presented here lays down the foundation for future structure–function correlation studies with this therapeutically relevant enzyme. Each reaction intermediate described in the catalytic cycle of apPol here represents a potential drug target.…”

Section: Discussionmentioning

confidence: 99%

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Transient State Kinetics of Plasmodium falciparum Apicoplast DNA Polymerase Suggests the Involvement of Accessory Factors for Efficient and Accurate DNA Synthesis

2022

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Plasmodium, the causative agent of malaria, belongs to the phylum Apicomplexa. Most apicomplexans, including Plasmodium, contain an essential nonphotosynthetic plastid called the apicoplast that harbors its own genome that is replicated by a dedicated organellar replisome. This replisome employs a single DNA polymerase (apPol), which is expected to perform both replicative and translesion synthesis. Unlike other replicative polymerases, no processivity factor for apPol has been identified. While preliminary structural and biochemical studies have provided an overall characterization of apPol, the kinetic mechanism of apPol's activity remains unknown. We have used transient state methods to determine the kinetics of replicative and translesion synthesis by apPol and show that apPol has low processivity and efficiency while copying undamaged DNA. Moreover, while apPol can bypass oxidatively damaged lesions, the bypass is error-prone. Taken together, our results raise the following question�how does a polymerase with low processivity, efficiency, and fidelity (for translesion synthesis) faithfully replicate the apicoplast organellar DNA within the hostile environment of the human host? We hypothesize that interactions with putative components of the apicoplast replisome and/or an as-yet-undiscovered processivity factor transform apPol into an efficient and accurate enzyme.

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Section: ■ Discussionmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Transient State Kinetics of Plasmodium falciparum Apicoplast DNA Polymerase Suggests the Involvement of Accessory Factors for Efficient and Accurate DNA Synthesis

2022

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“…Recent studies have validated apPOL as a viable antimalarial drug target, with the Malaria Box compound MMV666123 showing promising results [75]. Furthermore, nine small molecules (KU0263501, KU0036696, KU0260920, KU0007309, KU0241474, KU0177470, KU0261556, KU0001071, and KU0271653) have been reported to be potential inhibitors against apPOL [76]. Te apicoplast genome codes for RNA polymerase subunits, RpoB, RpoC1, and RpoC2, which make up the RNA polymerase required for DNA transcription to RNA and share homology with bacterial RNA polymerase [36].…”

Section: Exploiting the Apicoplast-resident Processes As An Antimalar...mentioning

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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“…contains unusual organelle called the apicoplast that evolutionarily related to the chloroplast and involves in a number of metabolic processes, including biosynthesis of fatty acids, iron–sulfur clusters, haem and isoprenoids 14,15 . An enzyme apicoplast DNA polymerase replicates and repairs the genome of apicoplast and as this parasite relies on apicoplast, so, any defects in apicoplast metabolism or its inability to multiply and divide, cause Plasmodium to die in the blood and liver stages of infection 16 . Therefore, Apicoplast DNA polymerase is considered a promising drug target for developing anti‐malaria drug.…”

Section: Introductionmentioning

confidence: 99%

“… 14 , 15 An enzyme apicoplast DNA polymerase replicates and repairs the genome of apicoplast and as this parasite relies on apicoplast, so, any defects in apicoplast metabolism or its inability to multiply and divide, cause Plasmodium to die in the blood and liver stages of infection. 16 Therefore, Apicoplast DNA polymerase is considered a promising drug target for developing anti‐malaria drug. Another promising drug target to develop anti‐malaria chemotherapy is the Plasmodium falciparum cysteine protease falcipain‐2, is one of four papain‐family cysteine proteases known as falcipains‐2 expressed by malaria parasite Plasmodium falciparum .…”

Section: Introductionmentioning

confidence: 99%

Antimalarial drug discovery against malaria parasites through haplopine modification: An advanced computational approach

Akash,

Abdelkrim,

Bayil

et al. 2023

J Cellular Molecular Medi

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The widespread emergence of antimalarial drug resistance has created a major threat to public health. Malaria is a life‐threatening infectious disease caused by Plasmodium spp., which includes Apicoplast DNA polymerase and Plasmodium falciparum cysteine protease falcipain‐2. These components play a critical role in their life cycle and metabolic pathway, and are involved in the breakdown of erythrocyte hemoglobin in the host, making them promising targets for anti‐malarial drug design. Our current study has been designed to explore the potential inhibitors from haplopine derivatives against these two targets using an in silico approach. A total of nine haplopine derivatives were used to perform molecular docking, and the results revealed that Ligands 03 and 05 showed strong binding affinity compared to the control compound atovaquone. Furthermore, these ligand‐protein complexes underwent molecular dynamics simulations, and the results demonstrated that the complexes maintained strong stability in terms of RMSD (root mean square deviation), RMSF (root mean square fluctuation), and Rg (radius of gyration) over a 100 ns simulation period. Additionally, PCA (principal component analysis) analysis and the dynamic cross‐correlation matrix showed positive outcomes for the protein‐ligand complexes. Moreover, the compounds exhibited no violations of the Lipinski rule, and ADMET (absorption, distribution, metabolism, excretion, and toxicity) predictions yielded positive results without indicating any toxicity. Finally, density functional theory (DFT) and molecular electrostatic potential calculations were conducted, revealing that the mentioned derivatives exhibited better stability and outstanding performance. Overall, this computational approach suggests that these haplopine derivatives could serve as a potential source for developing new, effective antimalarial drugs to combat malaria. However, further in vitro or in vivo studies might be conducted to determine their actual effectiveness.

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Discovery of small molecule inhibitors of Plasmodium falciparum apicoplast DNA polymerase

Cited by 10 publications

References 33 publications

Transient State Kinetics of Plasmodium falciparum Apicoplast DNA Polymerase Suggests the Involvement of Accessory Factors for Efficient and Accurate DNA Synthesis

Transient State Kinetics of Plasmodium falciparum Apicoplast DNA Polymerase Suggests the Involvement of Accessory Factors for Efficient and Accurate DNA Synthesis

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

Antimalarial drug discovery against malaria parasites through haplopine modification: An advanced computational approach

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