Essential Genes of the Parasitic Apicomplexa

Oberstaller, Jenna; Otto, Thomas D.; Rayner, Julian C.; Adams, John

doi:10.1016/j.pt.2020.11.007

Cited by 22 publications

(15 citation statements)

References 82 publications

(90 reference statements)

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“…These taxa-specific proteins are of particular importance because they are likely to be involved in parasite-specific biology and may define traits specific to parasites and the genus. Due to their absence in the human host, taxa-specific essential proteins and functions are also of high interest because they represent potential drug targets that could be specifically inhibited without harming the host (Oberstaller et al, 2021; Rancati et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Gene-by-gene screen of the unknown proteins encoded onP. falciparumchromosome 3

Kimmel

Schmitt

Sinner

et al. 2022

Preprint

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Taxa-specific proteins are key determinants defining the biology of all organisms and rep-resent prime drug targets in pathogens. How-ever, lacking comparability with proteins in other lineages makes them particularly diffi-cult to study. In malaria parasites this is exac-erbated by technical limitations. Here, we ana-lysed the cellular location, essentiality, func-tion and, in selected cases, interactome of all unknown non-secretory proteins encoded on an entire P. falciparum chromosome. The nu-cleus was the most common localisation, in-dicating it is a hotspot of parasite-specific bi-ology. More in-depth functional studies with four proteins revealed essential roles in DNA replication and mitosis. The novel mitosis pro-teins defined a possible orphan complex and a highly diverged complex needed for the spin-dle-kinetochore connection. Structure-function comparisons indicated that the taxa-specific proteins evolved by different mecha-nisms. This work demonstrates the feasibility of gene-by-gene screens to elucidate the biol-ogy of malaria parasites and reveal critical parasite-specific processes of interest as drug targets.

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Section: Introductionmentioning

confidence: 99%

Gene-by-gene screen of the unknown proteins encoded onP. falciparumchromosome 3

Kimmel

Schmitt

Sinner

et al. 2022

Preprint

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“…The development of higher-throughput experimental genetic approaches has increased the capacity for functional characterization of gene products as they relate to various phenotypes of interest ( Birnbaum et al, 2020 ; Cowell et al, 2018 ; Demas et al, 2018 ; Gnädig et al, 2020 ; Li et al, 2019 ; Oberstaller et al, 2021 ; Zhang et al, 2020 ), including drug resistance. Results from such genome-scale screens provide an opportunity to re-interpret previous findings of population-level genomic and transcriptomic studies for which the functional relevance of identified genes is not understood.…”

Section: Introductionmentioning

confidence: 99%

Integration of population and functional genomics to understand mechanisms of artemisinin resistance in Plasmodium falciparum

Oberstaller

Zoungrana

Bannerman

et al. 2021

International Journal for Parasitology: Drugs and Drug Resistan

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Resistance to antimalarial drugs, and in particular to the artemisinin derivatives and their partner drugs, threatens recent progress toward regional malaria elimination and eventual global malaria eradication. Population-level studies utilizing whole-genome sequencing approaches have facilitated the identification of regions of the parasite genome associated with both clinical and in vitro drug-resistance phenotypes. However, the biological relevance of genes identified in these analyses and the establishment of a causal relationship between genotype and phenotype requires functional characterization. Here we examined data from population genomic and transcriptomic studies in the context of data generated from recent functional studies, using a new population genetic approach designed to identify potential favored mutations within the region of a selective sweep (iSAFE). We identified several genes functioning in pathways now known to be associated with artemisinin resistance that were supported in early population genomic studies, as well as potential new drug targets/pathways for further validation and consideration for treatment of artemisinin-resistant Plasmodium falciparum. In addition, we establish the utility of iSAFE in identifying positively-selected mutations in population genomic studies, potentially accelerating the time to functional validation of candidate genes.

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“…Essential genes perform key cellular functions for the survival of pathogens [ 37 ]. The P. falciparum strain 3D7 essential genes information were obtained from the recently published articles [ 16 , 17 ] and total 3380 essential proteins were identified.…”

Section: Resultsmentioning

confidence: 99%

Analysing the essential proteins set of Plasmodium falciparum PF3D7 for novel drug targets identification against malaria

Ali

Wali

Jan

et al. 2021

Malar J

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Background Plasmodium falciparum is an obligate intracellular parasite of humans that causes malaria. Falciparum malaria is a major public health threat to human life responsible for high mortality. Currently, the risk of multi-drug resistance of P. falciparum is rapidly increasing. There is a need to address new anti-malarial therapeutics strategies to combat the drug-resistance threat. Methods The P. falciparum essential proteins were retrieved from the recently published studies. These proteins were initially scanned against human host and its gut microbiome proteome sets by comparative proteomics analyses. The human host non-homologs essential proteins of P. falciparum were additionally analysed for druggability potential via in silico methods to possibly identify novel therapeutic targets. Finally, the PfAp4AH target was prioritized for pharmacophore modelling based virtual screening and molecular docking analyses to identify potent inhibitors from drug-like compounds databases. Results The analyses identified six P. falciparum essential and human host non-homolog proteins that follow the key druggability features. These druggable targets have not been catalogued so far in the Drugbank repository. These prioritized proteins seem novel and promising drug targets against P. falciparum due to their key protein–protein interactions features in pathogen-specific biological pathways and to hold appropriate drug-like molecule binding pockets. The pharmacophore features based virtual screening of Pharmit resource predicted a lead compound i.e. MolPort-045–917-542 as a promising inhibitor of PfAp4AH among prioritized targets. Conclusion The prioritized protein targets may worthy to test in malarial drug discovery programme to overcome the anti-malarial resistance issues. The in-vitro and in-vivo studies might be promising for additional validation of these prioritized lists of drug targets against malaria.

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Essential Genes of the Parasitic Apicomplexa

Cited by 22 publications

References 82 publications

Gene-by-gene screen of the unknown proteins encoded onP. falciparumchromosome 3

Gene-by-gene screen of the unknown proteins encoded onP. falciparumchromosome 3

Integration of population and functional genomics to understand mechanisms of artemisinin resistance in Plasmodium falciparum

Analysing the essential proteins set of Plasmodium falciparum PF3D7 for novel drug targets identification against malaria

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