Host-directed therapy, an untapped opportunity for antimalarial intervention

Wei, Ling; Adderley, Jack; Leroy, Didier; Drewry, David H.; Wilson, Danny W.; Kaushansky, Alexis; Doerig, Christian

doi:10.1016/j.xcrm.2021.100423

Cited by 23 publications

(18 citation statements)

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“…The identification of PRDX6, a host RBC enzyme that is essential for P. falciparum blood stage growth, allows the development of completely novel strategies for pharmacological treatment and control of malaria. Approaches that target host enzymes for development of anti-malarial drugs are attractive because parasites cannot mutate the target gene to attain resistance (Wei et al, 2021). Thus, inhibitors that target host enzymes such as PRDX6 are less likely to face the problem of drug resistance and could play a critical role in malaria eradication efforts in the long term.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, co-treatment with Darapladib and artemisinin synergistically reduces survival of ART-resistant P. falciparum strains in a ring stage survival assay. The advantage of antimalarial drugs that target host enzymes has been recently highlighted (Wei et al, 2021). The studies reported here identify PRDX6 as a potential host-based drug target and may provide a strategy to overcome artemisinin resistance in P. falciparum .…”

Section: Introductionmentioning

confidence: 99%

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Human peroxiredoxin 6 is essential for malaria parasites and provides a host-based drug target

Wagner

Formaglio

Gorgette

et al. 2022

Preprint

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The uptake and digestion of host hemoglobin by malaria parasites during blood stage growth leads to significant oxidative damage of membrane lipids. Repair of lipid peroxidation damage is crucial for parasite survival. Here, we demonstrate that Plasmodium falciparum imports a host antioxidant enzyme, peroxiredoxin 6 (PRDX6), during hemoglobin uptake from the red blood cell cytosol. PRDX6 is a lipid peroxidation repair enzyme with phospholipase A2 (PLA2) activity. Inhibition of PRDX6 with a PLA2 inhibitor, Darapladib, increases lipid peroxidation damage in the parasite and disrupts transport of hemoglobin-containing vesicles to the food vacuole, causing parasite death. Furthermore, inhibition of PRDX6 synergistically reduces the survival of artemisinin-resistant parasites following co-treatment of parasite cultures with artemisinin and Darapladib. Thus, PRDX6 is a unique host-derived drug target for development of antimalarial drugs that could help overcome artemisinin resistance.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Human peroxiredoxin 6 is essential for malaria parasites and provides a host-based drug target

Wagner

Formaglio

Gorgette

et al. 2022

Preprint

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“…Decades of immune response studies converge on similar conclusions with regards to the need to understand much more about the intricate host–parasite relationships and immune responses that allow for sustained parasitism [ 19 , 46 – 48 ]. Such knowledge has the potential to reveal new immunological targets of intervention, whether against the parasite, or in the form of host-directed or adjunctive therapies, including repurposed drugs [ 395 , 396 ]. A greater understanding of the NAI responses that lead to partial (or possibly complete) protection is needed, as well as in-depth knowledge about the host and parasite receptor-ligand target molecules required for successful host cell invasion and parasitism, the immune cell types, factors, and pathways that become activated to ward off an infection, the parasite’s immune evasion tactics to overcome such immune activity, and the cascade of pathological consequences that follow.…”

Section: Twenty-first Century—turning Point In Malaria Researchmentioning

confidence: 99%

Systems biology of malaria explored with nonhuman primates

Galinski

2022

Malar J

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Abstract“The Primate Malarias” book has been a uniquely important resource for multiple generations of scientists, since its debut in 1971, and remains pertinent to the present day. Indeed, nonhuman primates (NHPs) have been instrumental for major breakthroughs in basic and pre-clinical research on malaria for over 50 years. Research involving NHPs have provided critical insights and data that have been essential for malaria research on many parasite species, drugs, vaccines, pathogenesis, and transmission, leading to improved clinical care and advancing research goals for malaria control, elimination, and eradication. Whilst most malaria scientists over the decades have been studying Plasmodium falciparum, with NHP infections, in clinical studies with humans, or using in vitro culture or rodent model systems, others have been dedicated to advancing research on Plasmodium vivax, as well as on phylogenetically related simian species, including Plasmodium cynomolgi, Plasmodium coatneyi, and Plasmodium knowlesi. In-depth study of these four phylogenetically related species over the years has spawned the design of NHP longitudinal infection strategies for gathering information about ongoing infections, which can be related to human infections. These Plasmodium-NHP infection model systems are reviewed here, with emphasis on modern systems biological approaches to studying longitudinal infections, pathogenesis, immunity, and vaccines. Recent discoveries capitalizing on NHP longitudinal infections include an advanced understanding of chronic infections, relapses, anaemia, and immune memory. With quickly emerging new technological advances, more in-depth research and mechanistic discoveries can be anticipated on these and additional critical topics, including hypnozoite biology, antigenic variation, gametocyte transmission, bone marrow dysfunction, and loss of uninfected RBCs. New strategies and insights published by the Malaria Host–Pathogen Interaction Center (MaHPIC) are recapped here along with a vision that stresses the importance of educating future experts well trained in utilizing NHP infection model systems for the pursuit of innovative, effective interventions against malaria.

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“…One key class of signalling molecules, protein kinases, have been successfully targeted to treat numerous diseases; for example, 62 kinase inhibitors have reached the market for the treatment for a variety of conditions (prominently cancer), and this number keeps increasing [ 7 ]. Protein kinases encoded by pathogens, as well as host kinases required for survival of intracellular pathogens, carry considerable potential as targets for the treatment of infectious diseases such as malaria [ 8 , 9 ]. Protein kinases catalyse the transfer of phosphate from adenosine triphosphate (ATP) to a substrate polypeptide, resulting in structural and functional changes to the target protein.…”

Section: Introductionmentioning

confidence: 99%

Comparative analysis of the kinomes of Plasmodium falciparum, Plasmodium vivax and their host Homo sapiens

Adderley

Doerig

2022

BMC Genomics

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Background Novel antimalarials should be effective across all species of malaria parasites that infect humans, especially the two species that bear the most impact, Plasmodium falciparum and Plasmodium vivax. Protein kinases encoded by pathogens, as well as host kinases required for survival of intracellular pathogens, carry considerable potential as targets for antimalarial intervention (Adderley et al. Trends Parasitol 37:508–524, 2021; Wei et al. Cell Rep Med 2:100423, 2021). To date, no comprehensive P. vivax kinome assembly has been conducted; and the P. falciparum kinome, first assembled in 2004, requires an update. The present study, aimed to fill these gaps, utilises a recently published structurally-validated multiple sequence alignment (MSA) of the human kinome (Modi et al. Sci Rep 9:19790, 2019). This MSA is used as a scaffold to assist the alignment of all protein kinase sequences from P. falciparum and P. vivax, and (where possible) their assignment to specific kinase groups/families. Results We were able to assign six P. falciparum previously classified as OPK or ‘orphans’ (i.e. with no clear phylogenetic relation to any of the established ePK groups) to one of the aforementioned ePK groups. Direct phylogenetic comparison established that despite an overall high level of similarity between the P. falciparum and P. vivax kinomes, which will help in selecting targets for intervention, there are differences that may underlie the biological specificities of these species. Furthermore, we highlight a number of Plasmodium kinases that have a surprisingly high level of similarity with their human counterparts and therefore not well suited as targets for drug discovery. Conclusions Direct comparison of the kinomes of Homo sapiens, P. falciparum and P. vivax sheds additional light on the previously documented divergence of many P. falciparum and P. vivax kinases from those of their human host. We provide the first direct kinome comparison between the phylogenetically distinct species of P. falciparum and P. vivax, illustrating the key similarities and differences which must be considered in the context of kinase-directed antimalarial drug discovery, and discuss the divergences and similarities between the human and Plasmodium kinomes to inform future searches for selective antimalarial intervention.

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Host-directed therapy, an untapped opportunity for antimalarial intervention

Cited by 23 publications

References 103 publications

Human peroxiredoxin 6 is essential for malaria parasites and provides a host-based drug target

Human peroxiredoxin 6 is essential for malaria parasites and provides a host-based drug target

Systems biology of malaria explored with nonhuman primates

Comparative analysis of the kinomes of Plasmodium falciparum, Plasmodium vivax and their host Homo sapiens

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