Plasmodial Kinase Inhibitors Targeting Malaria: Recent Developments

Mustière, Romain; Vanelle, Patrice; Primas, Nicolas

doi:10.3390/molecules25245949

Cited by 19 publications

(8 citation statements)

References 122 publications

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“…Putative parasite protein kinase PBANKA_1016200 is a membrane protein involved in protein phosphorylation and ATP binding. Even though it is dispensable in both P. berghei and P. falciparum , in general, protein kinases have been an attractive subset of proteins to be used as antimalarial targets (reviewed in reference 89 ).…”

Section: Resultsmentioning

confidence: 99%

Dual RNA Sequencing Meta-analysis in Plasmodium Infection Identifies Host-Parasite Interactions

2021

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Dual RNA sequencing (RNA-Seq) is the simultaneous transcriptomic analysis of interacting symbionts, for example, in malaria. Potential cross-species interactions identified by correlated gene expression might highlight interlinked signaling, metabolic, or gene regulatory pathways in addition to physically interacting proteins. Often, malaria studies address one of the interacting organisms—host or parasite—rendering the other “contamination.” Here we perform a meta-analysis using such studies for cross-species expression analysis. We screened experiments for gene expression from host and Plasmodium. Out of 171 studies in Homo sapiens, Macaca mulatta, and Mus musculus, we identified 63 potential studies containing host and parasite data. While 16 studies (1,950 samples) explicitly performed dual RNA-Seq, 47 (1,398 samples) originally focused on one organism. We found 915 experimental replicates from 20 blood studies to be suitable for coexpression analysis and used orthologs for meta-analysis across different host-parasite systems. Centrality metrics from the derived gene expression networks correlated with gene essentiality in the parasites. We found indications of host immune response to elements of the Plasmodium protein degradation system, an antimalarial drug target. We identified well-studied immune responses in the host with our coexpression networks, as our approach recovers known broad processes interlinked between hosts and parasites in addition to individual host and parasite protein associations. The set of core interactions represents commonalities between human malaria and its model systems for prioritization in laboratory experiments. Our approach might also allow insights into the transferability of model systems for different pathways in malaria studies. IMPORTANCE Malaria still causes about 400,000 deaths a year and is one of the most studied infectious diseases. The disease is studied in mice and monkeys as lab models to derive potential therapeutic intervention in human malaria. Interactions between Plasmodium spp. and its hosts are either conserved across different host-parasite systems or idiosyncratic to those systems. Here we use correlation of gene expression from different RNA-Seq studies to infer common host-parasite interactions across human, mouse, and monkey studies. First, we find a set of very conserved interactors, worth further scrutiny in focused laboratory experiments. Second, this work might help assess to which extent experiments and knowledge on different pathways can be transferred from models to humans for potential therapy.

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Section: Resultsmentioning

confidence: 99%

Dual RNA Sequencing Meta-analysis in Plasmodium Infection Identifies Host-Parasite Interactions

2021

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“…The inhibition of serine/arginine-rich proteins, result in protein-phosphorylating cyclin-dependent kinase also inhibiting the erythrocytic-stage replication ( Kern et al, 2014 ). Mustière et al (2020) have reviewed a number of inhibitors against plasmodial kinases.…”

Section: Invasion and Egress Of Merozoites And Inhibitionmentioning

confidence: 99%

Targeting the Plasmodium falciparum proteome and organelles for potential antimalarial drug candidates

Abugri¹,

Ayariga²,

Sunwiale³

et al. 2022

Heliyon

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“…Furthermore, CDPKs are critical for various physiological processes in the malaria parasite lifecycle [57] . Consequently, CDPKs have been considered as potentially good drug targets for the discovery of novel antimalarial agents (see reviews [18] , [77] , [83] . High throughput screening has led to the identification of different Pf CDPK1 targeting inhibitory scaffolds including 2,3,9-trisubstituted purines [59] , indolizines [68] and imidazopyridazines [68] , [47] , [4] , [22] , [23] , [66] ( Table 3 ).…”

Section: Targeting Cdpks Of Malaria Parasite For Drug Development and Functional Characterizationmentioning

confidence: 99%

CDPKs: The critical decoders of calcium signal at various stages of malaria parasite development

Sharma

Choudhury

Roy

et al. 2021

Computational and Structural Biotechnology Journal

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Plasmodial Kinase Inhibitors Targeting Malaria: Recent Developments

Cited by 19 publications

References 122 publications

Dual RNA Sequencing Meta-analysis in Plasmodium Infection Identifies Host-Parasite Interactions

Dual RNA Sequencing Meta-analysis in Plasmodium Infection Identifies Host-Parasite Interactions

Targeting the Plasmodium falciparum proteome and organelles for potential antimalarial drug candidates

CDPKs: The critical decoders of calcium signal at various stages of malaria parasite development

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