The proteasome as a target to combat malaria: hits and misses

Krishnan, Karthik; Williamson, Kim C.

doi:10.1016/j.trsl.2018.04.007

Cited by 37 publications

(24 citation statements)

References 77 publications

(91 reference statements)

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“…5A). Also, HS-Sensitive mutants shared an increased sensitivity to the proteasome inhibitor BTZ, consistent with laboratory observations connecting artemisinin MOA to the proteasome and clinical data that proteasome-inhibitors act synergistically with artemisinins 8, 19,20,21 . Overall, correlation of mutant phenotypic profiles across screens varied, with 16-45% having correlating phenotypes in at least one additional screen (Fig.…”

Section: Resultssupporting

confidence: 84%

The apicoplast link to fever-survival and artemisinin-resistance in the malaria parasite

Zhang¹,

Wang²,

Oberstaller³

et al. 2020

Preprint

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BackgroundThe emergence and spread of Plasmodium falciparum parasites resistant to front-line antimalarial artemisinin-combination therapies (ACT) threatens to erase the considerable gains against the disease of the last decade. We developed a new large-scale phenotypic screening pipeline and used it to carry out the first large-scale forward-genetic phenotype screen in P. falciparum to identify genes that allow parasites to survive febrile temperatures.ResultsScreening identified more than 200 P. falciparum mutants with differential responses to increased temperature. These mutants were more likely to be sensitive to artemisinin derivatives as well as to heightened oxidative stress. Major processes critical for P. falciparum tolerance to febrile temperatures and artemisinin included highly essential, conserved pathways associated with protein-folding, heat-shock and proteasome-mediated degradation, and unexpectedly, isoprenoid biosynthesis, which originated from the parasite’s algal endosymbiont-derived plastid, the apicoplast. Apicoplast-targeted genes in general were up-regulated in response to heat shock, as were other Plasmodium genes with orthologs in plant and algal genomes.ConclusionsPlasmodium falciparum parasites appear to exploit their innate febrile-response mechanisms to mediate resistance to artemisinin. Both responses depend on endosymbiotic cyanobacterium-related ancestral genes in the parasite’s genome, suggesting a link to the evolutionary origins of Plasmodium parasites in free-living ancestors.

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Section: Resultssupporting

confidence: 84%

The apicoplast link to fever-survival and artemisinin-resistance in the malaria parasite

Zhang¹,

Wang²,

Oberstaller³

et al. 2020

Preprint

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“…Another interesting clinical application of proteasome inhibition is in the treatment of malaria [232][233][234][235]. Malaria parasites contain their own form of the 26S proteasome in the cytoplasm and nucleus.…”

Section: Other Indications For Proteasome Inhibitorsmentioning

confidence: 99%

Proteasome Inhibitors: Harnessing Proteostasis to Combat Disease

Sherman

Li²

2020

Molecules

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The proteasome is the central component of the main cellular protein degradation pathway. During the past four decades, the critical function of the proteasome in numerous physiological processes has been revealed, and proteasome activity has been linked to various human diseases. The proteasome prevents the accumulation of misfolded proteins, controls the cell cycle, and regulates the immune response, to name a few important roles for this macromolecular “machine.” As a therapeutic target, proteasome inhibitors have been approved for the treatment of multiple myeloma and mantle cell lymphoma. However, inability to sufficiently inhibit proteasome activity at tolerated doses has hampered efforts to expand the scope of proteasome inhibitor-based therapies. With emerging new modalities in myeloma, it might seem challenging to develop additional proteasome-based therapies. However, the constant development of new applications for proteasome inhibitors and deeper insights into the intricacies of protein homeostasis suggest that proteasome inhibitors might have novel therapeutic applications. Herein, we summarize the latest advances in proteasome inhibitor development and discuss the future of proteasome inhibitors and other proteasome-based therapies in combating human diseases.

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“…A bioassay that tested 20 antimalarial drugs with a sex-specific readout reported increased sensitivity of male gametocytes to thiostrepton [ 130 ]. These studies suggest growing evidence of mitochondrial metabolism and proteasome pathways as emerging drug targets that hold the key for the development of novel transmission-blocking chemotherapeutic interventions [ 162 , 163 , 164 ]. Additionally, natural products from plant and microbial origins are being extensively investigated for the discovery of new antimalarial compounds [ 165 ].…”

Section: Antimalarial Drug Therapies and Gametocytesmentioning

confidence: 99%

Targeting Gametocytes of the Malaria Parasite Plasmodium falciparum in a Functional Genomics Era: Next Steps

2021

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Mosquito transmission of the deadly malaria parasite Plasmodium falciparum is mediated by mature sexual forms (gametocytes). Circulating in the vertebrate host, relatively few intraerythrocytic gametocytes are picked up during a bloodmeal to continue sexual development in the mosquito vector. Human-to-vector transmission thus represents an infection bottleneck in the parasite’s life cycle for therapeutic interventions to prevent malaria. Even though recent progress has been made in the identification of genetic factors linked to gametocytogenesis, a plethora of genes essential for sexual-stage development are yet to be unraveled. In this review, we revisit P. falciparum transmission biology by discussing targetable features of gametocytes and provide a perspective on a forward-genetic approach for identification of novel transmission-blocking candidates in the future.

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The proteasome as a target to combat malaria: hits and misses

Cited by 37 publications

References 77 publications

The apicoplast link to fever-survival and artemisinin-resistance in the malaria parasite

The apicoplast link to fever-survival and artemisinin-resistance in the malaria parasite

Proteasome Inhibitors: Harnessing Proteostasis to Combat Disease

Targeting Gametocytes of the Malaria Parasite Plasmodium falciparum in a Functional Genomics Era: Next Steps

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