2021
DOI: 10.1002/cbic.202100155
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Chemoproteomics for Plasmodium Parasite Drug Target Discovery

Abstract: Emerging Plasmodium parasite drug resistance is threatening progress towards malaria control and elimination. While recent efforts in cell‐based, high‐throughput drug screening have produced first‐in‐class drugs with promising activities against different Plasmodium life cycle stages, most of these antimalarial agents have elusive mechanisms of action. Though challenging to address, target identification can provide valuable information to facilitate lead optimization and preclinical drug prioritization. Recen… Show more

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Cited by 14 publications
(9 citation statements)
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“…Essentiality refers to how important a protein is for the parasite's survival, and druggability means how likely a drug can bind to a protein and cause a therapeutic effect. P. falciparum proteins that are essential and have high druggability indices are more likely to be effective antiplasmodial targets than those that are dispensable and have low druggability indices 4,17 . Essentiality data for proteins of related organisms were retrieved from the TDR database if P. falciparum speci c data was lacking.…”
Section: Essentiality and Druggability Index Of Predicted P Falciparu...mentioning
confidence: 99%
“…Essentiality refers to how important a protein is for the parasite's survival, and druggability means how likely a drug can bind to a protein and cause a therapeutic effect. P. falciparum proteins that are essential and have high druggability indices are more likely to be effective antiplasmodial targets than those that are dispensable and have low druggability indices 4,17 . Essentiality data for proteins of related organisms were retrieved from the TDR database if P. falciparum speci c data was lacking.…”
Section: Essentiality and Druggability Index Of Predicted P Falciparu...mentioning
confidence: 99%
“…genomic, transcriptomic, and proteomic data for P. falciparum transporters. The low coverage of the P. falciparum membrane proteome that complicates target profiling (Lu et al, 2021) may be overcome by large-scale culturing (Dalton et al, 2012) and more sensitive mass spectrometry techniques (McClure and Williams, 2018). Chemogenomic and transcriptional profiling of mutant-parasite libraries with altered drug sensitivities will further guide the determination of the mechanisms of drug action (Adjalley et al, 2015;Pradhan et al, 2015).…”
Section: Conclusion and Future Perspectivesmentioning
confidence: 99%
“…The lower number of genes representing the malaria transportome reported in earlier studies may be due to the lack of conventional transmembrane domains in some P. falciparum transporters (Desai, 2012) and difficult analysis by mass spectrometry. The reduced number of detected peptides (Lu et al, 2021) stems both from the typically low protein amounts extracted from parasite culture that are subjected to subcellular fractionation or immunoprecipitation and from the fact that membrane proteins such as transporters are less amenable to proteomics compared to soluble proteins. This has resulted in the conclusion that P. falciparum may have a reduced set of transporters compared to metazoan reference genomes (Weiner and Kooij, 2016;Martin, 2020).…”
Section: Introductionmentioning
confidence: 99%
“…Primaquine, an 8-amino quinoline derivative, is a therapeutically utilised inhibitor of the plasmodium parasite at the liver stage, it has a very high in-vitro IC50 (∼10 μM) [11]. However, the usage of primaquine has been limited by two factors including its limited oral bioavailability due to fast oxidative deamination to carboxyprimaquine and hemolytic anemia after the development of methemoglobinemia, which is most severe in persons with glucose 6-phosphate dehydrogenase insufficiency [12].…”
Section: Introductionmentioning
confidence: 99%