Dual-pharmacophore artezomibs hijack the Plasmodium ubiquitin-proteasome system to kill malaria parasites while overcoming drug resistance

Wen-hu, Zhan; Li, Da‐Qiang; Subramanyaswamy, Shubha Bevkal; Liu, Yi Jing; Yang, Changmei; Zhang, Hao; Harris, Jacob; Wang, Rong; Zhu, Songbiao; Rocha, Hedy L; Sherman, Julian; Qin, Junling; Herring, Mikayla; Simwela, Nelson V.; Waters, Andrew P.; Sukenick, George; Rodrı́guez, Ana; Deng, Haiteng; Nathan, Carl; Kirkman, Laura A.; Lin, Gang

doi:10.1016/j.chembiol.2023.04.006

Cited by 7 publications

(3 citation statements)

References 53 publications

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“…Examples of such ART-based hybrids include ones in which the second pharmacophoric group consists of 4-aminoquinolines, facilitating drug penetration inside the parasite and inhibiting heme polymerization synergistically with heme alkylation [27][28][29]. ARTs have also been conjugated with vinyl phosphonates to inhibit cysteine proteases and with peptidomimetics to inhibit proteasomes [29][30][31]. These hybrids display improved activity against drug-resistant parasites, even when the second moiety has no obvious activity on its own, ultimately indicating that a second pharmacophoric group and a chemical linker might induce conformational changes around the peroxide bond, protecting it from a rapid reaction [32][33][34].…”

Section: Introductionmentioning

confidence: 99%

Characterization of antimalarial activity of artemisinin-based hybrid drugs

Quadros,

Herrmann,

Manaranche

et al. 2024

Preprint

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In response to the spread of artemisinin (ART) resistance, ART-based hybrid drugs were developed and their activity profile was characterized against drug-sensitive and drug-resistant Plasmodium falciparum parasites. Two hybrids were found to display parasite growth reduction, stage-specificity, speed of activity, additivity of activity in drug combinations, and stability in hepatic microsomes of similar levels to those displayed by dihydroartemisinin (DHA). Conversely, the rate of chemical homolysis of the peroxide bonds is slower in the hybrids than in DHA. From a mechanistic perspective, heme plays a central role in the chemical homolysis of peroxide and in inhibiting heme detoxification and disrupting parasite heme redox homeostasis. The hybrid exhibiting slow homolysis of peroxide bonds was more potent in reducing the viability of ART-resistant parasites in a ring-stage survival assay than the hybrid exhibiting fast homolysis. However, both hybrids showed some limited activity against ART-induced quiescent parasites in the quiescent-stage survival assay. Our findings are consistent with previous results showing that slow homolysis of peroxide-containing drugs may retain activity against proliferating ART-resistant parasites. However, our data suggest that this property does not overcome the limited activity of peroxides in killing non-proliferating parasites in a quiescent state.

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Section: Introductionmentioning

confidence: 99%

Characterization of antimalarial activity of artemisinin-based hybrid drugs

Quadros,

Herrmann,

Manaranche

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

“…Examples of such ART-based hybrids include ones in which the second pharmacophoric group consists of 4-aminoquinolines, facilitating drug penetration inside the parasite and inhibiting hemozoin production synergistically with heme alkylation ( 27 – 29 ). ARTs have also been conjugated with vinyl phosphonates to inhibit cysteine proteases and with peptidomimetics to inhibit proteasomes ( 29 – 31 ). These hybrids display improved activity against drug-resistant parasites, even when the second moiety has no obvious activity on its own, ultimately indicating that a second pharmacophoric group and a chemical linker might induce conformational changes around the peroxide bond, protecting it from a rapid reaction ( 32 – 34 ).…”

Section: Introductionmentioning

confidence: 99%

Characterization of antimalarial activity of artemisinin-based hybrid drugs

Quadros,

Herrmann,

Manaranche

et al. 2024

Antimicrob Agents Chemother

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In response to the spread of artemisinin (ART) resistance, ART-based hybrid drugs were developed, and their activity profile was characterized against drug-sensitive and drug-resistant Plasmodium falciparum parasites. Two hybrids were found to display parasite growth reduction, stage-specificity, speed of activity, additivity of activity in drug combinations, and stability in hepatic microsomes of similar levels to those displayed by dihydroartemisinin (DHA). Conversely, the rate of chemical homolysis of the peroxide bonds is slower in hybrids than in DHA. From a mechanistic perspective, heme plays a central role in the chemical homolysis of peroxide, inhibiting heme detoxification and disrupting parasite heme redox homeostasis. The hybrid exhibiting slow homolysis of peroxide bonds was more potent in reducing the viability of ART-resistant parasites in a ring-stage survival assay than the hybrid exhibiting fast homolysis. However, both hybrids showed limited activity against ART-induced quiescent parasites in the quiescent-stage survival assay. Our findings are consistent with previous results showing that slow homolysis of peroxide-containing drugs may retain activity against proliferating ART-resistant parasites. However, our data suggest that this property does not overcome the limited activity of peroxides in killing non-proliferating parasites in a quiescent state.

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“… Summary Artezomibs (ATZs), dual-pharmacophore molecules comprising of artemisinin and a parasite proteasome inhibitor, hijack parasite ubiquitin proteasome system to transform into new proteasome inhibitors following the activation of artemisinin by heme. 1 Here, we present a protocol for using a fluorescent activity-based broad-spectrum proteasome inhibitor probe to study intracellular conversion of ATZ molecules into new proteasome inhibitors in malaria parasites. We describe steps for drug treatment and washout, parasite lysis, proteasome labeling, and visualization.…”

mentioning

confidence: 99%

Protocol for analysis of intracellular conversion of artezomib molecules into new proteasome inhibitors in Plasmodium falciparum parasites

Zhan,

Liu,

Kirkman

et al. 2024

STAR Protocols

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Dual-pharmacophore artezomibs hijack the Plasmodium ubiquitin-proteasome system to kill malaria parasites while overcoming drug resistance

Cited by 7 publications

References 53 publications

Characterization of antimalarial activity of artemisinin-based hybrid drugs

Characterization of antimalarial activity of artemisinin-based hybrid drugs

Characterization of antimalarial activity of artemisinin-based hybrid drugs

Protocol for analysis of intracellular conversion of artezomib molecules into new proteasome inhibitors in Plasmodium falciparum parasites

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